Substituted phthalazinones as neurotensin antagonists

ABSTRACT

Novel substituted phthalazinones of the formula (I) ##STR1## are useful as neurotensin antagonists.

This application is a U.S. national phase application based on PCT international application PCT/US93/10386 filed on Oct. 28, 1993, which is a continuation of U.S. Ser. No. 07/970,358 filed Nov. 2, 1992 (now abandoned), priority of which is claimed hereunder.

INTRODUCTION OF THE INVENTION

This invention relates to novel substituted phthalazinone compounds represented by formula I: ##STR2## which are antagonists of peptide hormone neurotensin. The invention is also concerned with the use of aforementioned neurotensin antagonists in the treatment of states meditated by neurotensin.

BACKGROUND OF THE INVENTION

Neurotensin (NT) is a tridecapeptide hormone (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu-OH), originally isolated from the bovine hypothalamus [Carraway, R. and Leeman, S. E., J. Biol. Chem., 248, 6854 (1973)], has subsequently been shown to be distributed in the brain [Uhl, G. R., et al., Proc. Natl. Acad. Sci. USA, 74, 4059-4063 (1977)], gastrointestinal tract [1). Kitabgi, P., Carraway, R. and Leeman, S. E., J. Biol. Chem., 251, 7053 (1976); 2). Carraway, R., Kitabgi, P., and Leeman, S. E., J. Biol. Chem., 253, 7996 (1978); 3).Helmstadler, V., Taugner, C., Feurle, G. E. and Frossman, W. G., Histochemistry, 53, 35-41 (1977)] and pancreas [Feurle, G. E. and Niestroj, S., Pancreas, 6, 202-207 (1991) and references cited therein] of various animals including human [Mai, J. K., et al., Neuroscience, 22, 499-524 (1987)]. Although the physiological role of neurotensin has not yet been clearly understood, this endogenous peptide participates in a wide spectrum of central [1). Prange, A. J. and Nemeroff, C. B., Annal. NY Acad. Sciences, 400, 368-375 (1982); 2). Stowe, Z. N.and Nemeroff, C. B., Life Sci., 49, 987-1002; (1991); 3) Kitabgi, P., Neurochem. Int., 14, 111-119 (1989); 4). Levant and Nemeroff, C. B., Current topics in Neuroendocrinology, 8, 231-262 (1988)] and peripheral [Leeman, S. E., Aronin, N. and Ferris, C., Hormone Res., 38, 93-132 (1982)] biological functions.

Neurotensin is also known to release mast cell histamine, indicating that antagonists will be useful in the treatment of allergic and inflammatory conditions, as well. [See, Rossei, S. S. and Miller, R. J., Life Sci., 31, 509-516 (1982) and Kurose, M. and Saeki, K., Eur. J. Pharmacol., 76, 129-136 (1981).]

Neurotensin, like most other peptides, is unable to cross the blood-brain barrier (BBB). However, certain peripheral effects of neurotensin have been observed after central administration of the peptide [Prange, A. J. and Nemeroff, C. B., Annal. NY Acad. Sciences, 400, 368-391 (1982)]. The direct application of neurotensin into the brain causes hypothermia, potentiation of barbiturate induced sedation, catalepsy. antinociception, blockade of psychostimulant-induced locomotor activity and reduced food consumption. In the central nervous system (CNS), neurotensin behaves as a neurotransmitter or neuromodulator [1) Uhl, G. R. and Snyder, S. H., Eur. J. Pharmacol., 41, 89-91 (1977); 2) Uhl, G. R., Annal. NY Acad. Sciences, 400, 132-149 (1982)], and has been shown to have close anatomical and biochemical associations with the dopaminergic (DA) system [Nemeroff, C. B., et al. Annal. NY Acad. Sciences, 400, 330-344 (1982)]. Neurotensin increases the synthesis and the turnover of DA in rat brain. Acute and chronic treatment with clinically efficacious antipsychotic drugs (e.g., haloperidol, chloropromazine) have consistently demonstrated an increase in neurotensin concentrations in the nucleus accumbens and striatum while phenothiazines that are not antipsychotics did not produce this increase. Behaviorally, neurotensin, after central administration, mimics the effects of systemically administered neuroleptics. However, unlike classical neuroleptics (which primarily acts on D₂ receptors), neurotensin fails to bind to dopamine receptors or inhibit cAMP accumulation following DA receptor activation. Neurotensin does not block the stereotypy induced by DA agonists. The post-mortem studies of patients with schizophrenia showed an increase in the level of neurotensin in the Brodman's area 32 of human brain [Nemeroff, C. B., et. al., Science., 221, 972-975 (1983) and references cited therein], which suggest possible roles of neurotensin in the pathophysiology of this disease. Neurotensin receptors have also been implicated in Parkinson's disease and progressive supranuclear palsy [Chinaglia, G. et al., Neuroscience, 39, 351-360 (1990)].

Of the total body neurotensin in many mammalian species, more than 80% is present in the gastrointestinal tract, especially in the distal small intestine in the endocrine like N-cells. In the gut, neurotensin stimulates pancreatic secretion [Sakamoto, T.,et al, Surgery, 96, 146-53 (1984)], inhibits gastric acid secretion and gastric emptying [Blackburn, A. M., Lancet, 1, 987-989 (1980)]. Neurotensin also stimulates the growth of small intestinal mucosa in an isolated defunctional loop of jejunum, which suggests a direct systemic effect of neurotensin in the gut. In addition, neurotensin can stimulate pancreatic exocrine secretion in mammals [Iwatsuki, K., et al., Clin. Expt. Pharmacol. Physiol., 18, 475-481 (1991) and references cited therein].

From the structural work, it is evident that the biological activity of neurotensin resides within the carboxy terminal five or six amino acid residues. The C-terminal hexapeptide NT⁸⁻¹³ has displayed full biological activity of the tridecapeptide. In contrast, all amino terminal partial sequences are essentially inactive [Leeman, S. E. and Carraway, R. E., Annal. NY Acad. Sciences, 400, 1-16 (1982)]. The C-terminal COOH group and two Arg residues are essential for the biological activity of NT⁸⁻¹³ as well as neurotensin. L-amino acids are required at positions-9, 10, 11 and 13, and only Arg⁸ can be replaced by D-Arg without loss of any activity. At the position-11, an aromatic amino acid is essential. Similarly, alkyl side-chains of Ile¹² and Leu¹³ are also necessary for full biological activity [Kitabgi, P., Annal. NY Acad. Sciences, 400, 37-53 (1982)]. Most of the analogues of neurotensin examined generally behaved as agonists. However, two analogues D-Trp¹¹ -NT and Tyr(Me)¹¹ -NT have displayed partial antagonist activity [Rioux, F. R.,et al., Eur. J. Pharmacol., 66, 373-379 (1980)].

Although there are reports of peptidic neurotensin antagonists, none are clinically useful, due to their short biological half life and limited oral bioavailability.

A European Patent Application, EP 477,049, disclosing 3-carboxamido-1,2-pyrazoles as non-peptidic neurotensin antagonists recently published.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel compounds of structural formula I: ##STR3## or a pharmaceutically acceptable salt thereof, wherein:

R¹ is:

(a) --NHSO₂ NHCOR⁹,

(b) --NHCONHSO₂ R⁹,

(c) --SO₂ NHR⁹,

(c) --SO₂ NHCOR⁹,

(d) --SO₂ NHCONR⁷ R⁹, or

(f) --SO₂ NHCOOR⁹ ;

R^(2a) and R^(2b) are each independently:

(a) H,

(b) Cl, Br, I, F,

(c) CF₃,

(d) C₁ -C₆ -alkyl,

(e) C₁ -C₆ -alkoxy,

(f) C₁ -C₆ -alkyl-S--,

(g) C₂ -C₆ -alkenyl,

(h) C₂ -C₆ -alkynyl,

(i) C₃ -C₇ -cycloalkyl,

(j) aryl, as defined in R⁴ (c) below, or

(k) aryl-C_(1-C) ₆ -alkyl as defined in R⁴ (c) below;

aryl is defined as phenyl or naphthyl, either unsubstituted or substituted with one or two substituents selected from the group consisting of Cl, F, Br, I, N(R⁷)₂, NR⁷ COOR⁹, NR⁷ CONR⁷ R⁹, CO₂ R⁷, CONR⁷ R⁹, C₁ -C₄ -alkyl, --(C₁ -C₄)alkyl-Y, NO₂, OH, CF₃, C₁ -C₄ -alkoxy, --S(O)_(x) --(C₁ -C₄)alkyl, and --(C₁ -C₄)alkyl-N-(CH₂ -CH₂)₂ Q,

R^(3a) is:

(a) H,

(b) Cl, Br, I, F,

(c) C₁ -C₆ -alkyl,

(d) C₁ -C₆ -alkoxy, or

(e) C₁ -C₆ -alkoxyalkyl;

R^(3b) is:

(a) H,

(b) Cl, Br, I, F,

(c) C₁ -C₆ -alkyl,

(d) C₃ -C₇ -cycloalkyl,

(e) C₁ -C₆ -alkoxy,

(f) CF₃,

(g) C₂ -C₆ -alkenyl, or

(h) C₂ -C₆ -alkynyl;

R⁴ is:

(a) H,

(b) C₁ -C₆ -alkyl optionally substituted with a substituent selected from the group consisting of: C₁ -C₄ -alkoxy, aryl, heteroaryl, --CON(R¹⁰)₂, --N(R¹⁰)₂, --O--COR¹⁰ and --COR¹⁰ or

(c) aryl,

(d) heteroaryl, as defined in R⁴ (c) above

(e) C₃ -C₇ -cycloalkyl, or

(f) --COaryl;

heteroaryl is defined as thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, thiazinyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, pyridazinyl, pyrazinyl, or pyrimidinyl and wherein the heteroaryl is unsubstituted or substituted with one or two substituents selected from the group consisting of: --OH, --SH, --C₁ -C₄ alkyl, --C₁ -C₄ -alkoxy, --CF₃, Cl, Br, F, I, --NO₂, --CO₂ H, --CO₂ -(C₁ -C₄ -alkyl), --NH₂, --NH(C₁ -C₄ -alkyl) and --N(C₁ -C₄ -alkyl)₂, NR⁷ COOR⁹ and NR⁷ CONR⁷ R⁹,

Q is: a single bond, --CH₂ --, O, NR⁷, or S(O)_(x) ;

Y is: COOR⁹, CN, NR⁷ COOR⁹ or CONR⁷ R⁹ ;

R⁵ and R⁶ are independently:

(a) H,

(b) C₁ -C₆ -alkyl, unsubstimted or substituted with a substituent selected from the group consisting of: --OH, -guanidino, C₁ -C₄ -alkoxy, --N(R⁷)₂, COOR⁷, --CON(R⁷)₂, --)--COR⁷, -aryl, as defined in R⁴ (c) above -heteroaryl, --S(O)_(x) -R⁹, -tetrazol-5-yl, --CONHSO₂ R⁹, --SO₂ NH-heteroaryl, as defined in R⁴ (d) above --SO₂ NHCOR⁹, --PO(OR⁷)₂, --PO(OR⁸)R⁷, --SO₂ NH--CN, --NR⁸ COOR⁹, morpholino, ##STR4## and --COR⁷, (c) --CO-aryl,

(d) --C₃ -C₇ -cycloalkyl,

(e) Cl, Br, I, F,

(f) --OH,

(g) --OR⁹,

(h)--C₁ -C₄ -perfluoroalkyl,

(i) --S(O)_(X) --R⁹,

(j) --COOR⁷,

(k) --SO₃ H,

(l) --NR⁷ R⁹,

(m) --NR⁷ COR⁹,

(n) --NR⁷ COOR⁹,

(o) --SO₂ NR⁷ R⁸,

(p) --NO₂,

(q) --NR⁷ SO₂ R⁹,

(r) --NR⁷ CONR⁷ R⁹,

(s) --OCONR⁹ R⁷,

(t) -aryl, as defined in R⁴ (c) above

(u) --NHSO₂ CF₃,

(v) --SO₂ NH-heteroaryl, as defined in R⁴ (d) above

(w) --SO₂ NHCOR⁹,

(x) --CONHSO₂ R⁹,

(y) --PO(OR⁷)₂,

(z) --PO(OR⁸)R⁷,

(aa) -tetrazol-5-yl,

(bb) --CONH(tetrazol-5-yl),

(cc) --COR⁷,

(dd) --SO₂ NHCN,

(ee) --CO-heteroaryl, as defined in R⁴ (d) above

(ff) --NR⁷ SO₂ NR⁹ R⁷,

(gg) --N[CH₂ CH₂ ]₂ NR¹¹,

(hh) --N[CH₂ CH₂ ]₂ O, or

(ii) -heteroaryl; as defined in R⁴ (d) above

x is: 0, 1, or2,

R⁷ is: H, C₁ -C₅ -alkyl, aryl, or --CH₂ -aryl, as defined in R⁴ (c) above;

R⁸ is: H, or C₁ -C₄ -alkyl;

R⁹ is:

(a) aryl, as defined in R⁴ (c) above

(b) heteroaryl, as defined in R⁴ (d) above

(c) C₃ -C₇ -cycloalkyl,

(d) C₁ -C₈ -alkyl, wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of: aryl, as defined in R⁴ (c) above, heteroaryl, as defined in R⁴ (d) above, --OH, --SH, C₁ -C₄ -alkyl, --O(C₁ -C₄ -alkyl), --S(C₁ -C₄ -alkyl), --CF₃, Cl, Br, F, I, --NO₂, --CO₂ H, --CO₂ --C₁ --C₄ -alkyl, --NH₂, --NR⁷ CO₂ R¹⁰, --NH(C₁ -C₄ -alkyl), --N(C₁ -C₄ -alkyl)₂, --PO₃ H₂, --PO(OH)(O--C₁ -C₄ -alkyl), --PO(OR⁸)R⁷, --NR⁷ COR¹⁰, --CONR⁷ R¹⁰, --OCONR⁷ R¹⁰, --SO₂ NR⁷ R¹⁰, --NR⁷ SO₂ R¹⁰, --N(CH₂ --CH₂)₂ Q and --CON(CH₂ --CH₂)₂ Q or

(e) perfluoro-C₁ -C₄ -alkyl;

R¹⁰ is:

(a) aryl, as defined in R⁴ (c) above,

(b) heteroaryl, as defined R⁴ (d) above,

(c) C₁ -C₆ -alkyl, wherein alkyl is unsubstituted or substituted with a substituent selected from the group consisting of: aryl, as defined in R⁴ (c) above, heteroaryl, as defined in R⁴ (d) above, --OH, --NH₂, --NH(C₁ -C₄ -alkyl), --N(C₁ -C₄ -alkyl)₂, --CO₂ R⁷, Cl, Br, F, I, and --CF₃, or

(d) perfluoro-C₁ -C₄ -alkyl;

R¹¹ is: C₁ -C₆ -alkyl, C₃ -C₇ -cycloalkyl, --CONR⁷ R⁸, heteroaryl, as defined in R⁴ (d) above, phenyl, --CO--C₃ -C₇ -cycloalkyl, or --CO--C₁ -C₆ -alkyl; and

r is: 1 or2.

One embodiment of the compounds of formula (I) are those compounds wherein:

R¹ is:

(a) --NHSO₂ NHCOR⁹, or

(b) --NHCONHSO₂ R⁹ ;

R^(2a) is: H;

R^(2b) is: H, F, Cl, CF₃, C₁ -C₆ -alkyl, C₂ -C₄ -alkenyl, or C₂ -C₄ -alkynyl, aryl, wherein aryl is as defined above or aryl-C₁ -C₆ -alkyl;

R^(3a) is: H;

R^(3b) is: H, F, Cl, CF₃, C₁ -C₄ -alkyl, C₂ -C₄ -alkenyl, C₂ -C₄ -alkynyl, or C₅ -C₆ -cycloalkyl;

R⁵ and R⁶ are each independently:

(a) H,

(b) C₁ -C₆ -alkyl unsubstimted or substituted with COOR⁷, OCOR⁷, OH, or aryl wherein aryl is as defined above,

(c) --OH,

(d) --NO₂,

(e) --NHCOR⁹,

(f) --C₁ -C₄ -alkoxy,

(g) --NHCO₂ R⁹,

(h) --NR⁷ R⁹,

(i) --Cl, F, Br,

(j) --CF₃,

(k) --CO₂ R⁷,

(l) --CO-aryl, wherein aryl is as defined above,

(m) --S(O)_(X) --C₁ -C₄ -alkyl,

(n) --SO₂ --NH--C₁ -C₄ -alkyl,

(o) --SO₂ --NH-aryl,

(p) --NHSO₂ CH₃,

(q) -aryl, wherein aryl is as defined above,

(r) --NHCONR⁷ R⁹,

(s) N[CH₂ CH₂ ]₂ NR¹¹, or

(t) --N[CH₂ CH]₂ O;

r is 1.

A class of this embodiment are those compounds of Formula (I) wherein:

R¹ is:

(a) --NHSO₂ NHCOR⁹, or

(b) --NHCONHSO₂ R⁹ ;

R⁴ is: H, (C₁ -C₆)-alkyl, aryl, wherein aryl is as defined above, aryl-(C₁ -C₆)-alkyl, or heteroaryl, wherein heteroaryl is as defined above as defined before; and

R⁵ and R⁶ are each independently: H, --C₁ -C₄ -alkyl, aryl, wherein aryl is as defined above, --NO₂, --NR⁷ R⁹, --NHCOOR⁹, --Cl, --CH₂ COOH, --S(O)_(X) --C₁ -C₄ -alkyl, NHCONR⁷ R⁹, NHCOR⁹, CO₂ R⁷, --F, N[CH₂ CH₂ ]₂ NR¹¹, or N[CH₂ CH₂ ]₂ O.

A second embodiment of the invention are the compounds of formula (I) wherein:

R¹ is:

(a) --SO₂ NHR⁹,

(b) --SO₂ NHCOR⁹,

(c) --SO₂ NHCONR⁷ R⁹, or

(d) --SO₂ NHCOOR⁹ ;

R^(2a) is: H;

R^(2b) is: H, F, Cl, CF₃, C₁ -C₆ -alkyl, C₂ -C₄ -alkenyl, or C₂ -C₄ -alkynyl, aryl or aryl-C₁ -C₆ -alkyl, wherein aryl is as defined above

R^(3a) is: H;

R^(3b) is: H, F, Cl, CF₃, C₁ -C₄ -alkyl, C₂ -C₄ -alkenyl, C₂ -C₄ -alkynyl, or C₅ -C₆ -cycloalkyl;

R⁵ and R⁶ are independently:

(a) H,

(b) C₁ -C₆ -alkyl unsubstimted or substituted with COOR⁷, OCOR⁷, OH, or aryl, wherein aryl is as defined above,

(c) --OH,

(d) --NO₂,

(e) --NHCOR⁹,

(f) --C₁ -C₄ -alkoxy,

(g) --NHCO₂ R⁹,

(h) --NR⁷ R⁹,

(i) --Cl, F, Br,

(j) --CF₃,

(k) --CO₂ R⁷,

(l) --CO-aryl wherein aryl is as defined above,

(m) --S(O)_(X) --C₁ -C₄ -alkyl,

(n) --SO₂ --NH--C₁ -C₄ -alkyl,

(o) --SO₂ --NH-aryl wherein aryl is as defined above,

(p) --NHSO₂ CH₃,

(q) -aryl, wherein aryl is as defined above,

(r) --NHCONR⁷ R⁹,

(s) --N[CH₂ CH₂ ]₂ NR¹¹, or

(t) --N[CH₂ CH₂ ]₂ O; and

r is: 1.

A class of this embodiment are those compounds of Formula (I) wherein:

R¹ is:

(a) --SO₂ NHR⁹,

(b) --SO₂ NHCOR⁹,

(c) --SO₂ NHCONR⁷ R⁹, or

(d) --SO₂ NHCOOR⁹ ;

R⁴ is: H, (C₁ -C₆)alkyl, aryl, wherein aryl is as defined above, aryl-(C₁ -C₆)alkyl, or heteroaryl wherein heteroaryl is as defined above; and

R⁵ and R⁶ are each independently: H, --C₁ -C₄ -alkyl, -aryl, wherein aryl is as defined above --NO₂, --NR⁷ R⁹, --NHCOOR⁹, Cl, --CH₂ COOH, --S(O)_(X) --C₁ -C₄ -alkyl, NHCONR⁷ R⁹, NHCOR⁹, CO₂ R⁷, --F, N[CH₂ CH₂ ]₂ NR¹¹, or N[CH₂ CH₂ ]₂).

Further exemplifying this class are the compounds indicated in Table I below.

                                      TABLE I                                      __________________________________________________________________________      ##STR5##                                                                      Cmpd. #                                                                              R.sup.4     R.sup.5                                                                            R.sup.6                                                                            R.sup.9                                              __________________________________________________________________________     1     H           H   H   (CH.sub.2).sub.5 NHBoc                               2     H           H   H   (CH.sub.2).sub.5 NH.sub.2                            3     Methyl      H   H   (CH.sub.2).sub.5 NHBoc                               4     Methyl      H   H   (CH.sub.2).sub.5 NH.sub.2                            5     n-Propyl    H   i-propyl                                                                           (CH.sub.2).sub.5 NHBoc                               6     n-Propyl    H   H   (CH.sub.2).sub.5 NHBoc                               7     n-Propyl    H   H   (CH.sub.2).sub.5 NH.sub.2                            8     i-Propyl    H   H                                                        cyclopropyl                                                                    9     i-Propyl    H   H   (CH.sub.2).sub.4 NHBoc                               10    i-Propyl    H   H   (CH.sub.2).sub.4 NH.sub.2                            11    Phenyl      H   H                                                        cyclopropyl                                                                    12    Phenyl      H   H   (CH.sub.2).sub.5 NHBoc                               13    Phenyl      H   H   (CH.sub.2).sub.5 NH.sub.2                            14    Phenyl      methyl                                                                             H   (CH.sub.2).sub.5 NHBoc                               15    Phenyl      methyl                                                                             H   (CH.sub.2).sub.5 NH.sub.2                            16    p-Toluyl    H   H   (CH.sub.2).sub.5 NHCOCH.sub.3                        17    p-Toluyl    H   methyl                                                                             (CH.sub.2).sub.5 NH.sub.2                            18    p-Toluyl    H   methyl                                                                             (CH.sub.2).sub.5 NHBoc                               19    4-Cl-Phenyl H   H   (CH.sub.2).sub.5 NHBoc                               20    4-Cl-Phenyl H   H   (CH.sub.2).sub.5 NH.sub.2                            21    4-Cl-Phenyl H   H   (CH.sub.2).sub.4 CON(CH.sub.3).sub.2                 22    4-Cl-Phenyl H   methyl                                                                             (CH.sub.2).sub.5 NHBoc                               23    4-Br-Phenyl H   H   (CH.sub.2).sub.5 NHBoc                               24    4-Br-Phenyl H   H   (CH.sub.2).sub.5 NH.sub.2                            25    4-F-Phenyl  H   H   (CH.sub.2).sub.5 NHBoc                               26    4-F-Phenyl  H   H   (CH.sub.2).sub.5 NH.sub.2                            27    4-OMe-Phenyl                                                                               H   H   (CH.sub.2).sub.5 NHBoc                               28    4-OMe-Phenyl                                                                               H   H   (CH.sub.2).sub.5 NH.sub.2                            29    p-Toluyl    H   H   (CH.sub.2).sub.5 NHBoc                               30    p-Toluyl    H   H   (CH.sub.2).sub.5 NH.sub.2                            31    p-Toluyl    H   H   (CH.sub.2).sub.6 NHBoc                               32    p-Toluyl    H   H   (CH.sub.2).sub.6 NH.sub.2                            33    p-Toluyl    H   H   (CH.sub.2).sub.3 NHBoc                               34    p-Toluyl    H   H   (CH.sub.2).sub.3 NH.sub.2                            35    p-Toluyl    H   H   (CH.sub.2).sub.4 NHBoc                               36    p-Toluyl    H   H   (CH.sub.2).sub.4 NH.sub.2                            37    p-Toluyl    H   H   (CH.sub.2).sub.6 OH                                  38    p-Toluyl    H   H   (CH.sub.2).sub.5 COOC.sub.2 H.sub.5                  39    p-Toluyl    H   H   (CH.sub.2).sub.4 COOH                                40    p-Toluyl    methyl                                                                             H   (CH.sub.2).sub.5 COOC.sub.2 H.sub.5                  41    p-Toluyl    H   H   (CH.sub.2).sub.6 CH.sub.3                            42    p-Toluyl    H   H   (CH.sub.2).sub.5 CONHCH.sub.3                        43    p-Toluyl    H   H   (CH.sub.2).sub.5 CON(CH.sub.3).sub.2                 44    p-Toluyl    H   H   (CH.sub.2).sub.4 CON(CH.sub.3).sub.2                 45    p-Toluyl    H   H   (CH.sub.2).sub.4 CON(CH.sub.2).sub.4                 46    p-Toluyl    H   H   (CH.sub.2).sub.4 CON(CH.sub.2).sub.5                 47    p-Toluyl    H   H   (CH.sub.2).sub.4CON(CH.sub.2 CH.sub.2).sub.2 O       48    p-Toluyl    H   H   (CH.sub.2).sub.4 CON(CH.sub.2 CH.sub.2).sub.2                                  NH                                                   49    p-Toluyl    H   H   (CH.sub.2).sub.4 CON(CH.sub.2 CH.sub.2).sub.2                                  NAc                                                  50    p-Toluyl    H   H   (CH.sub.2).sub.4 CON(CH.sub.2 CH.sub.2).sub.2                                  NCH.sub.3                                            51    p-Toluyl    H   H   (CH.sub.2).sub.6 CON(CH.sub.3).sub.2                 52    p-Toluyl    H   H   (CH.sub.2).sub.2 CH(NHBoc)COOtBu                     53    p-Toluyl    H   H                                                        2-thienyl                                                                      54    p-Toluyl    H   H                                                        3-furyl                                                                        55    p-Toluyl    H   H                                                        2-furyl                                                                        56    p-Toluyl    H   H   (CH.sub.2).sub.2 OCH.sub.3                           57    p-Toluyl    H   H   NH(CH.sub.2).sub.3 CH.sub.3                          58    p-Toluyl    H   H   NH(CH.sub.2).sub.5 CH.sub.3                          59    p-Toluyl    H   H   NH(CH.sub.2).sub.3 Cl                                60    p-Toluyl    H   H   NH(CH.sub.2).sub.2 -2-thienyl                        61    p-Toluyl    H   H   CH.sub.2 OCH.sub.2 CH.sub.3                          62    p-Toluyl    H   H   (CH.sub.2).sub.5 OH                                  63    p-Toluyl    H   H   NH(CH.sub.2).sub.5 CH.sub.3                          64    p-Toluyl    H   H   (CH.sub.2).sub.5 N(CH.sub.3).sub.2                   65    p-Toluyl    H   H   (CH.sub.2).sub.5 NHCH.sub.3                          66    1-Naphthyl  H   H   (CH.sub.2).sub.5 N(CH.sub.3).sub.2                   67    1-Naphthyl  H   H   (CH.sub.2).sub.5 CON(CH.sub.3).sub.2                 68    1-Naphthyl  H   H   (CH.sub.2).sub.4 CON(CH.sub.3).sub.2                 69    1-Naphthyl  H   H   (CH.sub.2).sub.5 NHBoc                               70    1-Naphthyl  H   H   (CH.sub.2).sub.5 NH.sub.2                            71    4-OMe-Phenyl                                                                               H   H   (CH.sub.2).sub.5 CON(CH.sub.3).sub.2                 72    4-OMe-Phenyl                                                                               H   H   (CH.sub.2).sub.4 CON(CH.sub.3).sub.2                 73    2-Naphthyl  H   H   (CH.sub.2).sub.5 N(CH.sub.3).sub.2                   74    2-Naphthyl  H   H   (CH.sub.2).sub.5 CON(CH.sub.3).sub.2                 75    2-Naphthyl  H   H   (CH.sub.2).sub.4 CON(CH.sub.3).sub.2                 76    2-Naphthyl  H   H   (CH.sub.2).sub.5 NHBoc                               77    2-Naphthyl  H   H   (CH.sub.2).sub.5 NH.sub.2                            78    Pentamethylphenyl                                                                          H   H   (CH.sub.2).sub.5 NH.sub.2                            79    Pentamethylphenyl                                                                          H   H   (CH.sub.2).sub.5 NHBoc                               80    Pentamethylphenyl                                                                          H   H   (CH.sub.2).sub.4 CON(CH.sub.3).sub.2                 81    2-pyridyl   H   H   (CH.sub.2).sub.4 CON(CH.sub.3).sub.2                 82    4-pyridyl   H   H   (CH.sub.2).sub.4 CON(CH.sub.3).sub.2                 83    2-Thienyl   H   H   (CH.sub.2).sub.4 CON(CH.sub.3).sub.2                 84    2-pyridyl   H   H   (CH.sub.2).sub.5 NHBoc                               85    2-pyridyl   H   H   (CH.sub.2).sub.5 NH.sub.2                            86    2-pyridyl   H   H   (CH.sub.2).sub.5 N(CH.sub.3).sub.2                   87    4-pyridyl   H   H   (CH.sub.2).sub.5 NHBoc                               88    4-pyridyl   H   H   (CH.sub.2).sub.5 NH.sub.2                            89    4-pyridyl   H   H   (CH.sub.2).sub.5 N(CH.sub.3).sub.2                   90    4-pyridyl   H   H   (CH.sub.2).sub.4 CON(CH.sub.3).sub.2                 91    2-Thienyl   H   H   (CH.sub.2).sub.4 CON(CH.sub.3).sub.2                 92    4-(N-Morpholinomethyl)-                                                                    H   H   (CH.sub.2).sub.5 NHBoc                                     phenyl                                                                   93    4-(N-Morpholinomethyl)-                                                                    H   H   (CH.sub.2).sub.5 NH.sub.2                                  phenyl                                                                   94    4-(N-Pyrrolidinomethyl)-                                                                   H   H   (CH.sub.2).sub.5 NHBoc                                     phenyl                                                                   95    4-(N-Pyrrolidinomethyl)-                                                                   H   H   (CH.sub.2).sub.5 NH.sub.2                                  phenyl                                                                   96    4-(N-Pyrrolidinomethyl)-                                                                   H   H   (CH.sub.2).sub.4 CON(CH.sub.3).sub.2                       phenyl                                                                   97    4-(N-Morpholinomethyl)-                                                                    H   H   (CH.sub.2).sub.4 CON(CH.sub.3).sub.2                       phenyl                                                                   98    p-Toluyl    H   H   (CH.sub.2).sub.3 CON(CH.sub.3).sub.2                 99    p-Toluyl    H   H   (CH.sub.2).sub.5 NHCON(CH.sub.3).sub.2               100   p-Toluyl    H   H   (CH.sub.2).sub.5 NHSO.sub.2 iPr                      101   p-Toluyl    H   H   (CH.sub.2).sub.3 NHCON(CH.sub.3).sub.2               102   p-Toluyl    H   H   NH(CH.sub.2).sub.3 CON(CH.sub.3).sub.2               103   p-Toluyl    H   H   (CH.sub.2).sub.3 NHCOCH.sub.3                        104   p-Toluyl    H   H   (CH.sub.2).sub.4 CONH.sub.2                          105   p-Toluyl    H   H   (CH.sub.2).sub.4 CONHCH.sub.3                        106   4-Cl-Phenyl H   H   (CH.sub.2).sub.4 CON(CH.sub.3).sub.2                 107   4-F-Phenyl  H   H   (CH.sub.2).sub.4 CON(CH.sub.3).sub.2                 108   2-CH.sub.3 CONH-Phenyl                                                                     H   H   CH.sub.2).sub.4 CON(CH.sub.3).sub.2                  __________________________________________________________________________

The terms "alkyl", "alkenyl", "alkynyl": and the like include both the straight chain and branched chain species of these generic terms wherein the number of carbon atoms in the species permit. Unless otherwise noted, the specific names for these generic terms shall mean the straight chain species. For example, the term "butyl" shall mean the normal butyl substituent, n-butyl.

For a general review of synthesis and reactivity of substituted phthalazinones and related compounds, see--M. Tishler and B. Stanovnik, Comprehensive Heterocyclic Chemistry, Vol. 3 (part 2B), 1-56 (1984) Eds: A. J. Boulton and A. Mckillop; Pergamon Press., and also N. R. Patel, Heterocyclic Compounds, Vol. 27, Chapter II, pages 376-446 (1973). Ed: R. N. Castle, John Wiley & Sons, and references cited therein.

Scheme 1 illustrates the preferred method for the preparation of substituted phthalazin-1-(2H)-ones. An appropriately substituted 2-acylbenzoic acid 1 or a similar starting material is reacted with hydrazine hydrate in an appropriate solvent such as an alcohol or acetic acid under reflux for 2-24 h to form the corresponding substituted phthalazin-1-(2H)-one 2. ##STR6##

Where R⁴ is H, alkyl or aryl, as defined before.

The keto acid 1 may be prepared from the appropriately substituted 2-bromobenzoic acid or a similar starting material using the methods described in the literature [W. E. Parham, C. K. Bradsher, K. J. Edger, J. Org. Chem., 46(6), 1057(1981) and references cited therein]. Alternatively, the keto acids may also be synthesized by procedures described by R. L. Shriner et al., J. Org. Chem., 16, 1064 (1951), and C. R. Hauser et al., J. Org. Chem., 23, 861 (1958).

A general method for the preparation of 2-alkyl-phthalazin-1-(2H)-ones of Formula I is illustrated in Scheme 2. An appropriately substituted phthalazin-1-(2H)-one 2 is alkylated with the appropriate alkyl halide 3 (or pseudo halide, such as tosylate, mesylate, triflate and the like) in the presence of an appropriate base such as alkali metal hydrides, carbonates, bicarbonates or an organic base (e.g., trialkylamines, morpholine and the like) in an appropriate polar solvent, such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, lower alkyl alcohols and the like. The alkylated material 4 may then be transformed into the desired compound of Formula I by removal of the protecting group present in R^(1a) followed by further transformation of the functional group, thus formed, into the desired R¹ group. Similarly, the R¹ a may also be directly transformed into the desired R¹ to give the compound of formula I. ##STR7##

The biphenyl alkylating agents 3 can be synthesized using the reactions and techniques described in published U.S. Pat. No. 5,126,342 (Merck & Co, Inc.).

Compounds of Formula I in which R¹ is SO₂ NHR⁹ or SO₂ NHCOR⁹ may be prepared according to the general methods described for such transformations in U.S. Pat. No. 5,126,342. More specifically these compounds may be prepared as outlined in Scheme 3. ##STR8##

The protected sulfonamide 5 (prepared as described in Scheme 2 using the alkylating agent 3, where R^(1a) is --SO₂ NH-tBu) is reacted with TFA, and the resulting free sulfonamide 6 is acylated with an appropriate acylimidazole (generated from the corresponding R⁹ COOH and carbonyldiimidazole) in the presence of DBU to form the acylsulfonamide 7.

Compounds of Formula I in which R¹ is SO₂ NHCOOR⁹ or SO₂ NHCONR⁷ R⁹ may be prepared according to methods outlined in Schemes 4 and 5. ##STR9##

The sulfonamide 6 may be reacted with an appropriate isocyanate (R⁹ NCO) or carbamoyl chloride (R⁷ R⁹ NCOCl) in the presence of an appropriate base to form the corresponding sulfonylureas 8. ##STR10##

Similarly, the sulfonamide 6 may be reacted with an appropriate alkyl or aryl chloroformate (R⁹ OCOCl) in the presence of an appropriate base such as pyridine to form the corresponding sulfonylcarbamate 9.

Compounds of Formula I, where R¹ is --NHSO₂ NHCOR⁹ may be prepared from the corresponding nitro precursor 10 (prepared according to Scheme 2, where R^(1a) =NO₂) as outlined in Scheme 6. The nitro group in 10 is reduced to the corresponding amine 11 which may then be reacted with t-butylsulfamoyl chloride to give the N-t-butylsulfamide 12. Removal of the t-butyl group followed by acylation may produce the desired acylsulfamides 13. Similarly, compound 12 may be reacted with an appropriate N-acylsulfamoyl chloride to give 13. ##STR11##

The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the functionality present on the heterocycle and in the reactants being employed should be consistent with the chemical transformations being conducted. Depending upon the reactions and techniques employed, optimal yields may require changing the order of synthetic steps or use of protecting groups followed by deprotection.

The compounds of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases; e.g., dicyclohexylamine salts, N-methyl-D-glutamine salts, salts with amino acids like arginine, lysine, and the like. Also, salts with organic and inorganic acids may be prepared; e.g., HCl, HBr, H₂ SO₄, H₃ PO₄, methanesulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic. The nontoxic, physiologically, acceptable salts are preferred, although other salts are also useful in isolating and/or purifying the product.

The salts can be formed by conventional means, such as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.

Neurotensin is a peptide hormone and the assays described below have been developed to identify neurotensin antagonists and to determine their efficacy in vitro. The following three assays have been employed for that purpose.

RAT FOREBRAIN RECEPTOR ASSAY

Male rats are sacrificed by decapitation following ether anesthetization. Forebrains are homogenized using a polytron in 20 volumes 50 mM Tris HCl, pH 7.4, and centrifuged at 50,000×g for 20 min. The final pellet is washed twice by rehomogenization and centrifugation as before. The final pellet is resuspended at a concentration of 8 mg tissue (wet weight) per 0.750 ml of 50 mM Tris HCl, pH 7.4, which also contains 1 mM EDTA, 4 mg/ml bacitracin, 5 mM levocabastine HCl, 1 mM phenanthroline, 10 mg/ml soybean trypsin inhibitor and 100 mM phenyl methyl sulfonyl fluoride. Assay tubes (13×100 mm polypropylene) receive 1) 100 μl buffer or 10 mM neurotensin (for non-specific binding) 2) 100 μl of 60 pM [¹²⁵ I]neurotensin 3) 20 μl test compounds 4) 750 μl tissue suspension and 5) enough buffer to bring final volume to 1 ml. After 30 minutes at room temp, the samples are filtered using a Brandel M24 cell harvestor with GF/B filtermats that have been presoaked in 0.2% polyethyleneimine for 2 hours. The tubes are rinsed with 3×4 ml of ice cold 10 mM Tris buffer (pH 7.4 at room temperature). The filter discs are placed in 12×75 mm polypropylene tubes for counting on a Packard Multi-Prias gamma counter.

HUMAN HT-29 CELL MEMBRANE ASSAY

HT-29 cells were routinely grown in 225 cm² Costar tissue culture flasks at 37° C. in a humidified atmosphere of 5% CO₂ /95% air in Dulbecco's modified Eagle's medium with high glucose containing 50 U/ml penicillin, 50 mg/ml streptomycin, 5% fetal bovine serum and 5% newborn calf serum. Cells were subcultured with 0.25% trypsin at a ratio of 1:6 with confluence being reached at 48 to 72 hrs. Cells from confluent flasks (approx. 1×108 cells/flask) were harvested by scraping. The cells were pelleted by centrifugation (1000×g, 5 min), resuspended in 50 mM Tris HCl, pH 7.4, and homogenized with a polytron (setting 7 for 10 sec.). Cell membranes were washed twice by centrifugation (50,000×g, 15 min) and rehomogenized. The resulting pellet was either frozen at -70° C. for future use or run directly in the assay by resuspending at a concentration of 0.5×106 cells per 0.750 ml of assay buffer (50 mM Tris HCl, pH 7.4, containing 1 mM EDTA, 40 mg/ml bacitracin, 1 mM phenanthroline, 10 mg/ml soybean trypsin inhibitor and 100 mM phenylmethylsulfonyl fluoride).

Assay tubes (13×100 mm polypropylene) receive 1) 100 μl buffer or 10 mM neurotensin (for non-specific binding) 2) 100 μl of 60 pM [¹²⁵ I]neurotensin 3) 20 μl test compounds 4) 750 μl cell membrane suspension and 5) enough buffer to bring final volume to 1 ml. After 30 minutes at room temperature, the samples are filtered using a Brandel M24 cell harvestor with GF/B filtermats that have been presoaked in 0.2% polyethyleneimine for 2 hours. The tubes are rinsed with 3×4 ml of ice cold 10 mM Tris buffer (pH 7.4 at room temperature). The filter discs are placed in 12×75 mm polypropylene tubes for counting on a Packard Multi-Prias gamma counter. [The above assay is derived from the assay described in Kitabgi, P. et al., Molecular Pharmacology, 18, 11-19 (1980)].

NEUROTENSIN BINDING ASSAY TO HUMAN FRONTAL CORTEX

Post-mortem human brain is obtained through the National Disease Research Interchange (Philadelphia, PA). The donors were without psychiatric or neurological abnormalities. Frontal cortex is dissected free of white matter and homogenized using a polytron in 20 volumes 50 mM Tris HCl, pH 7.4, and centrifuged at 50,000×g for 20 min. The resulting pellet is washed twice by rehomogenization and centrifugation as before. The final pellet is resuspended at a concentration of 8 mg tissue (wet weight) per 0.750 ml of 50 mM Tris HCl, pH 7.4, which also contains 1 mM EDTA, 4 mg/ml bacitracin, 1 mM phenanthroline, 10 mg/ml soybean trypsin inhibitor and 100 mM phenyl methyl sulfonyl fluoride. Assay tubes (13×100 mm polypropylene) receive 1) 100 μl buffer or 10 mM neurotensin (for non-specific binding) 2) 100 μl of 60 pM [¹²⁵ I]neurotensin 3) 20 μl test compounds 4) 750 μl tissue suspension and 5) enough buffer to bring final volume to 1 ml. After 30 minutes at room temp, the samples are filtered using a Brandel M24 cell harvestor with GF/B filtermats that have been presoaked in 0.2% polyethyleneimine for 2 hours. The tubes are rinsed with 3×4 ml of ice cold 10 mM Tris buffer (pH 7.4 at room temperature). The filter discs are placed in 12×75 mm polypropylene tubes for counting on a Packard Multi-Prias gamma counter.

Using the methodology described above, representative compounds of the invention were evaluated and all were found to exhibit an activity of at least IC₅₀ <50μM thereby demonstrating and confirming the utility of the compounds of the invention as effective neurotensin antagonists.

Thus, the compounds of the present invention are useful in attenuating the effect of peptide hormone neurotensin, and hence in the treatment of conditions that are caused by altered levels of neurotensin in humans. These compounds are of value in the treatment of a variety of central nervous system disorders, such as psychoses, depression, Alzheimer's disease and anxiety. These compounds may also be expected to be useful in the treatment of gastrointestinal disorders such as gastroesophageal reflux disorder (GERD), irritable bowel syndrome, diarrhea, cholic, ulcer, GI tumors, dyspepsia, pancreatitis and esophagitis.

About 1 to 100 mg. of compound or mixture of compounds of Formula I or a physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.

Illustrative of the adjuvants which can be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the unit dosage unitform is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as required.

The following examples illustrate the preparation of the compounds of formula (I) and their incorporation into pharmaceutical compositions and as such are not to be considered as limiting the invention set forth in the claims appended hereto.

All ¹ H-NMR spectra were recorded on a Varian XL-200 or XL-400 Fourier Transform spectrometer. Chemical shifts are reported as (parts per million) downfield from tetramethylsilane. Mass spectra were obtained from the Merck & Co, Inc. mass spectral facility in Rahway, N.J.. Analytical TLC was conducted on E. M. Merck precoated silica plates (0.25 mm on glass, Kieselgel 60 F254) with UV and/or iodine visualization. Flash chromatography was conducted using E. Merck silica gel (mesh 200-400). All reactions were carried out under an atmosphere of dry nitrogen under standard conditions unless specified otherwise.

EXAMPLE 1 Synthesis of Phthalazin-1(2H)-ones: (A General Description)

To a suspension or a solution of an appropriate 2-acylbenzoic acid (available from a commercial source or prepared according to the literature procedure cited earlier)(1 mMol) in ethanol (5 ml) was added hydrazinc hydrate (5 mMol), and the resulting mixture was refluxed for 2-6 h. The reaction was cooled to room temperature, and the solid precipitated was filtered, washed with water and then cold ethanol. The resulting solid was dried in vacuo to give the desired phthalazin-1-(2H)-one which was crystallized from ethanol or any other appropriate solvent. Alternatively, the reaction mixture was concentrated to give the crude product which was then purified by trituration with water followed by crystallization from an appropriate solvent to give the desired phthalazin-1-(2H)-one.

Table II lists representative examples of phthalazin-1(2H)-ones prepared according to the procedure outlined in Example 1.

                  TABLE II                                                         ______________________________________                                          ##STR12##                                                                     Compound #                                                                             R.sup.4      Melting Point.sup.a                                       ______________________________________                                         2A      methyl       221-222° C. (ethanol)                              2C      phenyl       232-233° C. (ethanol)                              2D      p-toluyl     259-260° C. (ethanol)                              2E      (4-Cl)phenyl 267° C. (toluene)                                  2F      1-naphthyl   261° C. (ethanol)                                  2G      pentamethylphenyl                                                                           276° C.                                            2H      2-pyridyl    .sup.1 H-NMR, FAB MS: 224 (M + H)                         2I      i-propyl     156-157° C. (ethanol)                              2J      (4-OMe)phenyl                                                                               240-241° C.                                        2K      (4-F)phenyl  268° C.                                            2L      H            .sup.1 H-NMR, FAB MS: 147 (M + H)                         ______________________________________                                          .sup.a Recrystallization solvent.                                        

EXAMPLE 2 Preparation of 4-p-toluyl-2-(2'-aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one. Step 1. 4-p-toluyl-2-(2'-t-butylaminosulfonyl)-biphen-4-yl)methyl-phthalazin-1-(2H)-one (Alkylation of substituted phthalazin-1-(2H)-one)

To a suspension of 4-p-toluyl-phthalazin-1-(2H)-one [compound 2D] (2.36 g, 10 mMol) in toluene (50 mL) were added 2:5 N aqueous NaOH (4 mL) and Triton B (1 mL) followed by 2-(4'-bromomethylbiphenyl)-t-butylsulfonamide [prepared according to the procedure described in U.S. Pat. No. 5,126,342] (4.2 g, 11 mMol). The mixture was stirred at 85° C. for 12 h and then cooled to room temperature. The reaction was diluted with ethylacetate (100 mL), and the organic phase was washed with water (3×50 mL), and then dried over MgSO₄. The ethylacetate layer was filtered and concentrated in vacuo to a small volume (˜10 mL). Dry ether (100 mL) was added and the precipitate formed was filtered and dried. The crude product was then recrystallized from hot ethylacetate to give the desired product 4-p-toluyl-2-(2'-t-butylaminosulfonyl)-biphen-4-yl)methyl-phthalazin-1-(2H)-one as white crystalline solid (4.3 g).

¹ H-NMR (CDCl₃): δ 8.49 (m, 1H), 8.15 (d,1H), 7.76 (m, 3H), 7.15-7.60 (m,11H), 5.50 (s, 2H), 3.51 (s, 1H), 2.45 (s, 3H), 0.91 (s, 9H). FAB-MS: (m/e) 538 (M+H).

Step 2. 4-p-toluyl-2-(2'-aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one (Removal of the t-butyl group):

A solution of 4-p-toluyl)-2-(2'-t-butylaminosulfonyl)-biphen-4-yl)methyl-phthalazin-1-(2H)-one (2.7 g, 5.02 mMol) in trifluoroacetic acid (20 mL) was stirred at room temperature for 12-15 h. The solvent was removed in vacuo, and the residue was treated with cold aqueous saturated NaHCO₃. The precipitate formed was filtered and washed with water and then dried. The solid (2.4 g) was triturated with 50% ether in ethyl acetate (20 mL) at room temperature and filtered to give the desired sulfonamide 4-p-toluyl-2-(2'-aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one as white amorphous solid (2.2 g).

¹ H-NMR (CDCl₃): Δ8.49 (m, 1H), 8.15 (d,1H), 7.76 (m, 3H), 7.15-7.60 (m,11H), 5.50 (s, 2H), 3.81 (s, 2H), 2.45 (s, 3H). FAB-MS: (m/e) 482 (M+H).

Employing the procedures outlined above in Example 2, the following phthalazinone derivatives (Table III) were prepared.

Table III

                  TABLE III                                                        ______________________________________                                          ##STR13##                                                                     Examples  R.sup.4      NMR      Mass Spect                                     ______________________________________                                         3         phenyl       Yes      468 (M + H)                                    4         (4-Cl)phenyl Yes      502, 504 (M + H)                               5         pentamethylphenyl                                                                           Yes      538 (M + H)                                    6         1-naphthyl   Yes      518 (M + H)                                    7         methyl       Yes      406 (M + H)                                    8         n-propyl     Yes      422 (M + H)                                    9         2-pyridyl    Yes      469 (M + H)                                    ______________________________________                                    

EXAMPLE 10 Acylation of Sulfonamide 4-p-toluyl-2-(2'-(6-(N-t-butoxycarbonyl)aminohexanoyl)-aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one.

To a solution of 6-(N-t-butoxycarbonyl)aminohexanoic acid (2.88 g, 12.45 mMol) in dry tetrahydrofuran (THF) (25 mL) was added carbonyl diimidazole (2.1 g, 12.45 mMol). The mixture was heated at 65° C. for 3 h. After cooling to room temperature, a solution of the sulfonamide 4-p-toluyl-2-(2'-(6-(N-t-butoxy-carbonyl)amino-hexanoyl)aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one (obtained in Example 2) (2.0 g, 4.15 mMol) and 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) (1.86 mL,12.45 mMol) in THF (20 mL) was added. The solution was stirred at 50° C. for 18 hr. then concentrated to dryness in vacuo. 5% Citric acid solution was added and the mixture extracted with ethyl acetate three times. The combined organic phase was washed with brine, dried (over magnesium sulfate) and the solvent removed in vacuo. The residue was pre-absorbed on silica gel and purified by flash chromatography using chloroform-methanol-NH₄ OH (150:10:1) to give the titled acyl sulfonamide as a white amorphous solid, which was recrystallized from diethyl ether/hexane (2.3 g).

¹ H-NMR (CDCl₃): δ 8.50 (m, 1H), 8.22 (d,1H), 7.78 (m, 3H), 7.15-7.60 (m,11H), 5.52 (s, 2H), 3.0 (m, 2H), 2.45 (s, 3H), 1.84 (t, 2H), 1.44 (s, 9H), 1.1-1.4 (m, 6H). FAB-MS: (m/e) 695 (M+H).

The following analogs of 4-p-toluyl-2-(2'-(6-(N-t-butoxycarbonyl)aminohexanoyl)aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one (Table IV) were prepared by using the procedure described in Example 10.

                  TABLE IV                                                         ______________________________________                                          ##STR14##                                                                     Examples   R.sup.4   NMR        Mass Spect.                                    ______________________________________                                         11         phenyl    X          681 (M + H)                                    12         (4-Cl)phenyl                                                                             X          715, 717 (M + H)                               13         methyl    X          619 (M + H)                                    14         n-propyl  X          647 (M + H)                                    ______________________________________                                    

EXAMPLE 15 4-p-toluyl-2-(2'-(6-aminohexanoyl)aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one.

To a solution of 4-p-toluyl-2-(2'-(6-(N-t-butoxycarbonyl)-aminohexanoyl)aminosulfonyl)biphen-4-yl)-methyl-phthalazin-1-(2H)-one (obtained in Example 10) (2.0 g, 2.88 mMol) in methylene chloride (10 mL) was added a saturated solution of hydrogen chloride in ethyl acetate (10 mL), and the mixture stirred at room temperature for 4 h. The volatile components of the mixture were removed in vacuo and the product was precipitated with dry ether. The hygroscopic solid was filtered, washed with dry ether and dried in vacuo. The product was then recrystallized from (methanol/ether) to give the amine hydrochloride of the titled compound (1.8 g) as white powder.

¹ H-NMR (CD₃ OD): δ 8.50 (m, 1H), 8.22 (d,1H), 7.78 (m, 3H), 7.15-7.60 (m,11H), 5.52 (s, 2H), 3.2 (m, 2H), 2.45 (s, 3H), 1.84 (t, 2H), 1.2 (m, 6H). FAB-MS: (m/e) 595 (M+H).

Similarly, the following analogs of 4-p-toluyl-2-(2'-(6-aminohexanoyl)aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one (Example 15) were also prepared.

                  TABLE V                                                          ______________________________________                                          ##STR15##                                                                     Examples   R.sup.4   NMR        Mass spect.                                    ______________________________________                                         16         phenyl    X          581 (M + H)                                    17         (4-Cl)phenyl                                                                             X          615, 617 (M + H)                               18         methyl    X          519 (M + H)                                    19         n-propyl  X          547 (M + H)                                    ______________________________________                                    

EXAMPLE 20 4-p-toluyl-2-(2'-(6-(N,N-dimethylamino)hexanoyl)aminosulfonyl)-biphen-4-yl)methyl-phthalazin-1-(2H)-one.

The amine (from Example 15) (10 mg, 0.017 mmol), 30% formaldehyde solution (1 mL) and formic acid (0.4 mL) were heated together at 100° C. for 2 hr. The mixture was concentrated to dryness in vacuo. The residue was pre-absorbed on silica gel and chromatographed (0-10% methanol/methylene chloride, 1% ammonia) to give the titled dimethylamine compound (5.9 mg, 56%) (for spectral data see Table VI).

EXAMPLE 21 4-p-toluyl-2-(2'-(4-(N-t-butoxycarboxamido)butanoyl) aminosulfonyl)-biphen-4-yl)methyl-phthalazin-1-(2H)-one.

Carbonyl diimidazole (49 mg, 0.3 mmol) was added to a solution of t-BOC-aminobutyric acid (61 mg, 0.3 mmol) in tetrahydrofuran (THF) (3 mL) under nitrogen at room temperature. The mixture was heated at 65° C. for 3 hr. After cooling to room temperature, a solution of the sulfonamide (obtained in Example 2) (48 mg, 0.1 mmol)and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (37 μL, 0.25 mmol) in THF (3 mL) was added. The solution was heated at 50° C. for 18 hr. then concentrated to dryness in vacuo. 5% Citric acid solution was added and the mixture extracted with ethyl acetate three times. The combined organic phase was washed with brine, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was pre-absorbed on silica gel and chromatographed (0-10% methanol/methylene chloride) to give the titled acyl sulfonamide which was recrystallized from diethyl ether/hexane (32 mg, 48%) (for spectral data see Table VI).

EXAMPLE 22 4-p-toluyl-2-(2'-(4-(N,N-dimethylcarboxamido)butanoyl)amino-sulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one.

The titled dimethyl amide was synthesized from the sulfonamide (Example 2) and dimethylamidobutyric acid using the procedure outlined for Example 21. Chromatography (0-5% methanol/methylene chloride) followed by recrystallization (ethyl acetate/diethyl ether) gave the desired dimethyl amide in 51% yield (for spectral data see Table VI).

EXAMPLE 23 4-p-toluyl-2-(2'-(5-ethoxycarbonyl-pentanoyl)aminosulfonyl) biphen-4-yl)methyl-phthalazin-1-(2H)-one.

The titled ethyl ester was synthesized from the sulfonamide (Example 2) and adipic acid mono-ethyl ester using the procedure outlined for Example. 21. Chromatography (0-5% methanol/methylene chloride, 0.5% ammonia) followed by recrystallization (ethyl acetate/diethyl ether) gave the desired ethyl ester in 48% yield (for spectral data see Table VII).

EXAMPLE 24 4-p-toluyl-2-(2'-(5-carboxy-pentanoyl)aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one.

2M Lithium hydroxide solution (0.9 mL) was added to a stirred solution of the ethyl ester (Example 23) (300 mg, 0.47 mmol) in THF (15 mL) and water (3 mL) at room temperature. After stirring for 3 hr., 2M lithium hydroxide solution (0.9 mL) was added and stirring continued for 18 hr. The solution was concentrated in vacuo. 5% Citric acid was added and the mixture extracted with chloroform three times. The combined organic phase was washed with brine, dried (magnesium sulfate) and the solvent removed in vacuo to give the titled carboxylic acid (245 mg, 86%) (for spectral data see Table VII).

EXAMPLE 25 4-p-toluyl-2-(2'-(5-(N-morpholinocarbonyl)pentanoyl)aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one.

Carbonyl diimidazole (32 mg, 0.2 mmol) was added to a stirred solution of the carboxylic acid (Example 24) (40 mg, 0.066 mmol) in THF (3 mL) under nitrogen at room temperature. The solution was heated at 65° C. for 3 hr. After cooling to room temperature, morpholine (9 μL, 0.1 mmol) was added and the mixture heated at 50° C. for 18 hr. The solution was concentrated to dryness in vacuo. 5% Citric acid solution was added and the mixture extracted with ethyl acetate three times. The combined organic phase was washed with brine, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was pre-absorbed on silica gel and chromatographed (0-5% methanol/methylene chloride) to give the titled morpholino amide compound (15 mg, 33%) (for spectral data see Table VII).

EXAMPLE 26 4-p-toluyl-2-(2'-(5-(N,N-dimethylcarboxamido)pentanoyl)aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one.

The titled dimethyl amide was synthesized from the carboxylic acid (Example 24) and dimethylamine using the procedure outlined for Example 25. Chromatography (0-3% methanol/methylene chloride) afforded the dimethyl amide (15.5 mg, 37%) (for spectral data see Table VII).

EXAMPLE 27 4-p-toluyl-2-(2'-(6-(N -acetamido)hexanoy1)aminosulfonyl)-biphen-4-yl)methyl-phthalazin-1-(2H)-one.

Acetic anhydride (0.5 mL) followed by dimethylamino-pyridine (3 mg) was added to the amine hydrochloride (obtained from Example 15) (30 mg, 0.048 mmol) under nitrogen at room temperature. The solution was stirred at room temperature for 18 hr. then water added. The solid which precipitated was isolated by filtration and dried in vacuo. Recrystallization (ethyl acetate/diethyl ether) gave the titled acetamide (14.5 mg, 48%) (for spectral data see Table VII).

EXAMPLE 28 4-p-toluyl-2-(2'-(6-(N,N-dimethyl carbamoyl)hexanoyl )aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one.

DBU (66 μL, 0.441 mmol) was added to the amine hydrochloride (Example 15) (80 mg, 0.127 mmol) in THF (3 mL) under nitrogen at 0° C. Dimethylcarbamyl chloride (17.5 μL, 0.190 mmol) was added and stirring continued at 0° C. for 3 hr. 5% Citric acid solution was added and the mixture extracted with ethyl acetate four times. The combined organic phase was washed with water, brine, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was chromatographed (4% methanol/methylene chloride) to give the titled dimethyl urea (56 mg, 66%) (for spectral data see Table VII).

EXAMPLE 29 4-p-toluyl-2-(2'-(6-(N-iso-propylsulfonamido)hexanoyl)aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one.

DBU (35 μL, 0.24 mmol) was added to the amine hydrochloride (Example 15) (50 mg, 0.08 mmol) in THF (3 mL) under nitrogen at 0° C. Iso-propylsulfonyl chloride (13 μL, 0.035 mmol) was added and stirring continued at 0° C. for 3 hr. The solution was concentrated in vacuo then 5% citric acid solution added. The mixture was extracted with ethyl acetate four times. The combined organic phase was washed with brine, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was pre-absorbed on silica gel and chromatographed (0-10% methanol/methylene chloride) to give the iso-propylsulfonamide (28 mg, 50%) (for spectral data see Table VIII).

EXAMPLE 30 4-p-toluyl-2-(2'-(4-aminobutanoyl)aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one.

A saturated solution of hydrogen chloride in ethyl acetate (1 mL) was added to the t-Boc-compound (obtained from Example 21) (61 mg, 0.091 mmol) and the mixture stirred at room temperature for 1 hr. The volatile components of the mixture were removed in vacuo and the residue recrystallized (ethyl acetate/diethyl ether) to give the titled amine as the hydrochloride salt (38 mg, 74%) (for spectral data see Table VIII).

EXAMPLE 31 4-p-toluyl-2-(2'-(4-(N,N-dimethylcarbamoyl)butanoyl)aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one.

DBU (28 μL, 0.25 mmol) was added to the amine hydrochloride (Example 30) (45 mg, 0.07 mmol) in THF (1.5 mL) under nitrogen at 0° C. Dimethylcarbamyl chloride (10 μL, 0.11 mmol) was added and stirring continued at 0° C. for 5 hr. The solution was concentrated in vacuo then 5% citric acid solution added. The mixture was extracted with ethyl acetate four times. The combined organic phase was washed with brine, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was pre-absorbed on silica gel and chromatographed (0-10% methanol/methylene chloride) to give the titled dimethyl urea (16 mg, 36%) (for spectral data see Table VIII).

EXAMPLE 32 4-p-toluyl-2-(2'-(5-(N-pyrrolidinocarbonyl)pentanoyl)aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one.

The titled pyrrolidine amide was synthesized from the carboxylic acid (Example 24) and pyrrolidine using the procedure outlined for Example 25. The crude product was pre-absorbed on silica gel and chromatographed (0-10% methanol/methylene chloride) to give the pyrrolidine amide (29 mg, 67%) (for spectral data see Table VIII).

EXAMPLE 33 4-p-toluyl-2-(2'-(3-(N,N-dimethylcarboxamido)propylaminocarbonyl)-aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one.

DBU (29 μL, 0.20 mmol) followed by carbonyl diimidazole (48.8 mg, 0.30 mmol) was added to 3-(dimethylamido)butyl amine hydrochloride (50 mg, 0.30 mmol) in THF (3 mL) under nitrogen at room temperature. After stirring at room temperature for 2.5 hr., a solution of the sulfonamide (Example 2) (48 mg, 0.10 mmol) and DBU (45 μL, 0.30 mmol) was added and the mixture stirred at room temperature for a further 18 hr. The solution was concentrated in vacuo then 5% citric acid solution added. The mixture was extracted with ethyl acetate four times. The combined organic phase was washed with brine, dried (magnesium sulfate) and the solvent removed in vacuo. Recrystallization (ethyl acetate/diethyl ether) gave the titled sulfonyl urea (18 mg, 28%) (for spectral data see Table VIII).

EXAMPLE 34 4-p-toluyl-2-(2'-(hexylaminocarbonylaminosulfonyl)biphen-4-yl)methylphthalazin-1-(2H)-one

DBU (37 μL, 0.25 mmol) was added to a stirred solution of the free sulfonamide (Example 2) (48 mg, 0.10 mmol) in THF (3 mL) under nitrogen at room temperature. After stirring for 0.5 hr. hexyl isocyanate (27 μL, 0.25 mmol) was added and the mixture stirred for 18 hr. The solvent was removed in vacuo then 5% citric acid solution added. The mixture was extracted with ethyl acetate three times. The combined organic phase was washed with brine, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was pre-absorbed on silica gel and chromatographed (5% methanol/methylene chloride, 0.5% ammonia) to give the titled sulfonyl urea that was recrystallized from ethyl acetate/hexane (9.1 mg, 15%) (for spectral data see Table IX).

EXAMPLES 35-37

Examples 35-37 were prepared using the procedure outlined for Example 34 (See Table IX).

EXAMPLES 38-47

Examples 38-47 were prepared using appropriate procedures as outlined for Examples 1-33 (See Table IX).

                                      TABLE VI                                     __________________________________________________________________________      ##STR16##                                                                                              NMR                                                                        Benzyl                                                                             Tolyl                                                 Exam-                                                                              R.sup.9 Aromatic Protons                                                                            Methyl                                                                             R Group                                                                              MS                                          ples.                                                                              (NMR solvent)                                                                          Protons  (s, 2H)                                                                            (s, 3H)                                                                            Protons                                                                              (FAB)                                       __________________________________________________________________________     20  (CH.sub.2).sub.5 NMe.sub.2                                                             8.45(m, 1H)                                                                             5.50                                                                               2.44                                                                               3.34(m, 2H)                                                                          623.4                                                   8.15(d, 1H)      2.66(s, 6H)                                                                          (M + H)                                                 7.83(m, 3H)      1.84(t, 2H)                                           (CD.sub.3 OD/CDCl.sub.3)                                                               7.58-7.18(m, 11H)                                                                               1.51(t, 2H)                                                                    1.24(m, 4H)                                       21  (CH.sub.2).sub.3 NHBoc                                                                 8.48(m, 1H)                                                                             5.52                                                                               2.44                                                                               2.95(m, 2H)                                                                          669.5                                                   8.23(d, 1H)      1.82(t, 2H)                                                                          (M + H)                                         (CDCl.sub.3)                                                                           7.78(m, 3H)      1.51(m, 2H)                                                   7.62-7.25(m, 11H)                                                                               1.41(s, 9H)                                       22  (CH.sub.2).sub.3 CONMe.sub.2                                                           8.49(m, 1H)                                                                             5.51                                                                               2.44                                                                               2.89(s, 3H)                                                                          623.9                                           (CDCl.sub.3)                                                                           8.25(d, 1H)      2.87(s, 3H)                                                                          (M + H)                                                 7.79(m, 3H)      2.21(t, 2H)                                                   7.62-7.26(m, 11H)                                                                               1.93(t, 2H)                                                                    1.66(m, 2H)                                       __________________________________________________________________________

                                      TABLE VII                                    __________________________________________________________________________                                      NMR                                                                       Benzyl                                                                              Tolyl                                               R.sup.9     Aromatic  Protons                                                                             Methyl                                                                              R Group                                                                               MS                                Examples                                                                             (NMR solvent)                                                                              Protons   (s, 2H)                                                                             (s, 3H)                                                                             Protons                                                                               (FAB)                             __________________________________________________________________________     23    (CH.sub.2).sub.4 COOEt                                                                     8.50(m, 1H)                                                                              5.51 2.45 4.07(q, 2H)                                                                           638.4                                   (CDCl.sub.3)                                                                               8.25(d, 1H)         2.12(t, 2H)                                                                           (M + H)                                             7.80(m, 3H)         1.80(t, 2H)                                                7.60-7.24(m, 11H)   1.37(m, 4H)                                                                    1.20(t, 3H)                              24    (CH.sub.2).sub.4 COOH                                                                      8.50(m, 1H)                                                                              5.57 2.45 2.31(t, 2H)                                                                           610.4                                   (CDCl.sub.3)                                                                               8.26(m, 1H)         1.93(t, 2H)                                                                           (M + H)                                             7.81(m, 3H)         1.61(m, 2H)                                                7.61-7.24(m, 11H)   1.45(m, 2H)                              25                                                                                    ##STR17##  8.48(m, 1H) 8.25(d, 1H) 7.80(m, 3H) 7.60-7.25(m,                                         5.50 2.44 3.65(m, 4H) 3.56(m, 2H) 3.36(m, 2H)                                            .16(t, 2H) 1.86(t, 2H) 1.39(m,                                                        679.5 (M + H)                     26    (CH.sub.2).sub.4 CONMe.sub.2                                                               8.50(m, 1H)                                                                              5.50 2.44 2.91(s, 3H)                                                                           637.0                                   (CDCl.sub.3)                                                                               8.25(d, 1H)         2.89(s, 3H)                                                                           (M + H)                                             7.81(m, 3H)         2.16(t, 2H)                                                7.62-7.24(m, 11H)   1.87(t, 2H)                                                                    1.40(m, 4H)                              27    (CH.sub.2).sub.5 NHCOMe                                                                    8.48(m, 1H)                                                                              5.51 2.44 3.12(m, 2H)                                                                           637                                     (CDCl.sub.3)                                                                               8.24(d, 1H)         1.91(s, 3H)                                                                           (M + H)                                             7.80(m, 3H)         1.77(t, 2H)                                                7.64-7.25(m, 11H)   1.34(m, 4H)                                                                    1.11(m, 2H)                              28    (CH.sub.2).sub.5 NHCONMe.sub.2                                                             8.44(m, 1H)                                                                              5.51 2.43 3.02(m, 2H)                                                                           665.9                                   (CD.sub.3 OD/CDCl.sub.3)                                                                   8.17(d, 1H)         2.82(s, 6H)                                                                           (M + 1)                                             7.83(m, 3H)         1.78(t, 2H)                                                7.65(m, 11H)        1.31(m, 4H)                                                                    1.08(m, 2H)                              __________________________________________________________________________

                                      TABLE VIII                                   __________________________________________________________________________                                    NMR                                                                       Benzyl                                                                              Tolyl                                                 R.sup.9   Aromatic  Protons                                                                             Methyl                                                                              R Group                                                                               MS                                  Examples                                                                             (NMR solvent)                                                                            Protons   (s, 2H)                                                                             (s, 3H)                                                                             Protons                                                                               (FAB)                               __________________________________________________________________________     29    (CH.sub.2).sub.5 NHSO.sub.2 iPr                                                          8.48(m, 1H)                                                                              5.52 2.45 4.45(m, 1H)                                                                           701                                       (CDCl.sub.3)                                                                             8.24(d, 1H)         3.04(m, 2H)                                                                           (M + H)                                             7.80(m, 3H)         1.76(t, 2H)                                                7.62-7.24(m, 11H)   1.43(m, 2H)                                                                    1.35(m, 2H)                                                                    1.33(d, 6H)                                                                    1.18(m, 2H)                                30    (CH.sub.2).sub.3 NH.sub.2.HCl                                                            8.46(m, 1H)                                                                              5.54 2.46 2.79(t, 2H)                                                                           567.8                                     (CD.sub.3 OD)                                                                            8.16(d, 1H)         1.93(t, 2H)                                                                           (M + H)                                             7.92-7.85(m, 3H)    1.67(m, 2H)                                                7.67-7.30(m, 11H)                                              31    (CH.sub.2).sub.3 NHCONMe.sub.2                                                           8.47(m, 1H)                                                                              5.54 2.44 3.05(m, 2H)                                                                           638.2                                     (CDCl.sub.3)                                                                             8.25(d, 1H)         2.80(s, 6H)                                                                           (M + H)                                             7.77(m, 3H)         1.85(t, 2H)                                                7.57-7.26(m, 11H)   1.53(m, 2H)                                32                                                                                    ##STR18##                                                                               8.48(m, 1H) 8.25(d, 1H) 7.76(m, 3H) 7.57-7.36(m,                                         5.50 2.44 3.40(t, 2H) 3.31(t, 2H) 2.13(t, 2H)                                            1.89(m, 4H) 1.86(m, 2H) 1.39(m,                                                       663.2 (M + H)                       33    NH(CH.sub.2).sub.3 CONMe.sub.2                                                           8.48(m, 1H)                                                                              5.50 2.44 3.08(m, 2H)                                                                           638.3                                     (CDCl.sub.3)                                                                             8.16(d, 1H)         2.91(s, 3H)                                                                           (M + H)                                             7.77(m, 3H)         2.88(s, 3H)                                                7.56-7.26(m, 11H)   2.18(t, 2H)                                                                    1.69(m, 2H)                                __________________________________________________________________________

                  TABLE IX                                                         ______________________________________                                                                Nmr      MS                                             Examples  R.sup.9      Spectrum (FAB)                                          ______________________________________                                         34        NH(CH.sub.2).sub.5 CH.sub.3                                                                 X        581.8 (M + H)                                  35        NH(CH.sub.2).sub.3 CH.sub.3                                                                 X        609.6 (M + H)                                  36        NH(CH.sub.2).sub.3 Cl                                                                       X        601.8 (M + H)                                  37        NH(CH.sub.2)2-                                                                              X        635.3 (M + H)                                            2-Thienyl                                                            38        (CH.sub.2).sub.2 CH-                                                                        X        768.2 (M + H)                                            (COOtBu)NHBoc                                                        39        2-Thienyl    X        592.6 (M + H)                                  40        3-Furyl      X        576.8 (M + H)                                  41        (CH.sub.2).sub.2 OCH.sub.3                                                                  X        568.8 (M + H)                                  42        2-Furyl      X        576.7 (M + H)                                  43        CH.sub.2 OCH.sub.2 CH.sub.3                                                                 X        568.8 (M + H)                                  44        (CH.sub.2).sub.5 OH                                                                         X        596.9 (M + H)                                  45        (CH.sub.2).sub.3 NHCOMe                                                                     X        609.6 (M + H)                                  46        (CH.sub.2).sub.4 CONH.sub.2                                                                 X        609.5 (M + H)                                  47        (CH.sub.2).sub.4 CONHMe                                                                     X        623.5 (M + H)                                  ______________________________________                                    

EXAMPLE 48 Step 1: 4-(Morpholinomethyl)phenyl-2-[(2'-t-butylamino-sulfonyl)biphen-4-yl]methyl-phthalazin-1-(2H)-one.

A mixture of 4-p-toluyl-2-[(2'-t-butylaminosulfonyl)-biphen-4-yl]methyl-phthalazin-1-(2H)-one (0.27 g, 0.5 mMol), N-bromo-succinimide (0.09 g, 0.5 mMol) and azaisobutyro-nitrile (AIBN) (0.01 g) was refluxed for 3 h and then cooled down to room temperature. The mixture was filtered and the filtrate concentrated in vacuo to give a foam (0.3 g). The foam was dissolved in methylene chloride (5 mL) and cooled in an ice-bath. Morpholine (1 mL) was then added, and the mixture was stirred at room temperature for 15 h. The reaction mixture was concentrated in vacuo and the residue obtained was purified by flash chromatography [silica-gel using initially ethyl acetate-hexane (1:2) and then ethyl acetate-hexane (2:1)] to give the titled product as white solid (0.16 g).

¹ H-NMR(CDCl₃): δ 8.52 (m, 1H), 8.15 (d,1H), 7.79 (m, 3H), 7.36-7.65 (m,10H), 7.23 (m, 1H), 5.52 (s, 2H), 3.75 (t, 4H), 3.60(s, 2H), 3.51 (s, 1H), 2.52 (t, 4H), 0.91 (s, 9H). FAB-MS: (m/e) 609 (M+H).

Step 2: 4-(Morpholinomethyl)phenyl-2-[(2'-(6-(N-t-butyloxy carbonylamino)hexanoyl)aminosulfonyl)-biphen-4-yl]methyl-phthalazin-1-(2H)-one.

4-(Morpholinomethyl)phenyl-2-[(2'-aminosulfonyl)-biphen-4-yl]methyl-phthalazin-1-(2H)-one [prepared from 4-(Morpholinomethyl)phenyl-2- [(2'-t-butylaminosulfonyl)biphen-4-yl]methyl-phthalazin-1-(2H)-one according to the procedure described in Example 2; Step 2] (0.1 g, 0.18 mMol) was reacted in THF (3 mL) with the acyl-imidazole [prepared from N-t-Boc-aminohexanoic acid (0.083 g, 0.36 mMol) and N,N-carbonyldiimidazole (0.06 g, 0.36 mMol)] and DBU (0.053 mL), according to the procedure described in Example 10. The titled compound was obtained as a foam (0.12 g), after purification of the crude product by flash chromatography (silica-gel, chloroform-methanol-NH₄ OH-100:10:1).

¹ H-NMR (CDCl₃): δ 8.50 (m, 1H), 8.22 (d,1H), 7.78 (m, 3H), 7.15-7.60 (m,11H), 5.52 (s, 2H), 3.75 (t, 4H), 3.60(s, 2H), 3.0 (m, 2H), 2.52 (t, 4H), 1.84 (t, 2H), 1.44 (s, 9H), 1.1-1.4 (m, 6H). FAB-MS: (m/e) 780 (M+H).

Step 3: 4-(Morpholinomethyl)phenyl-2-[(2'-(6-aminohexanoyl)-aminosulfonyl)-biphen-4-yl]methyl-phthalazin-1-(2H)-one.

4-(Morpholinomethyl)phenyl-2- [(2'-(6-(N-t-butyloxy-carbonylamino)hexanoyl)aminosulfonyl)-biphen-4-yl]-methyl-phthalazin-1-(2H)-one, obtained in step 2, (0.10 g) was dissolved in a mixture of methylene chloride (1 mL) and anhydrous trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 1 h then concentrated in vacuo to dryness. Dry ether was added and the solid obtained was filtered and dried to give the titled compound as the ditrifluoroacetic acid salt (0.08 g).

¹ H-NMR (CD₃ OD): δ 8.50 (m, 1H), 8.22 (d,1H), 7.78 (m, 3H), 7.15-7.60 (m,11H), 5.52 (s, 2H), 3.75 (t, 4H), 3.60(s, 2H), 3.0 (m, 2H), 2.52 (t, 4H), 1.84 (t, 2H), 1.2-1.4 (m, 6H). FAB-MS: (m/e) 680 (M+H)

EXAMPLE 49 Typical Pharmaceutical Compositions Containing a Compound of the Invention [e.g. 4-p-toluyl-2-(2'-(5-(N,N-dimethyl-carboxamido)-pentanoyl)aminosulfonyl)biphen-4-yl)methyl-phthalazin-1-(2H)-one (Example 26)]. A: Dry Filled Capsules Containing 50 mg of Active Ingredient Per Capsule

    ______________________________________                                         Ingredient        Amount per capsule (mg)                                      ______________________________________                                         Title compound of Example 26                                                                     50                                                           Lactose           149                                                          Magnesium stearate                                                                               1                                                            Capsule (size No. 1)                                                                             200                                                          ______________________________________                                    

The title compound of Example 26 can be reduced to a No. 60 powder and the lactose and magnesium stearate can then be passed through a No. 60 blotting cloth onto the powder. The combined ingredients can then be mixed for about 10 minutes and filled into a No. 1 dry gelatin capsule.

B: Tablet

A typical tablet would contain the title compound of Example 26 (25 mg), pregelatinized starch USP (82 mg), microcrystalline cellulose (82 mg)and magnesium stearate (1 mg).

C: Suppository

Typical suppository formulations for rectal administration can contain the title compound of Example 26 (1-25 mg), butylated hydroxyanisole (0.08-1.0 mg), disodium calcium acetate (0.25-0.5 mg), and polyethylene glycol (775-1600 mg). Other suppository formulations can be made by substituting, for example, butylated hydroxytoluene (0.04-0.08 mg) for the disodium calcium acetate and a hydrogenated vegetable oil (675-1400 mg) such as Suppocire L, Wecobee FS, Wecobee M, Witepsols, and the like, for the polyethylene glycol.

D: Injection

A typical injectable formulation would contain the title compound of Example 26 (5.42 mg), sodium phosphate dibasic anhydrous (11.4 mg) benzyl alcohol (0.01 ml) and water for injection (1.0 ml). 

What is claimed is:
 1. A compound of structural formula I: ##STR19## or a pharmaceutically acceptable salt thereof, wherein: R¹ is:(a) --NHSO₂ NHCOR⁹, (b) --NHCONHSO₂ R⁹, (c) --SO₂ NHR⁹, (d) --SO₂ NHCOR⁹, (e) --SO₂ NHCONR⁷ R⁹, or (f) --SO₂ NHCOOR⁹ ; R^(2a) and R^(2b) are each independently:(a) H, (b) Cl, Br, I, F, (c) CF₃, (d) C₁ -C₆ -alkyl, (e) C₁ -C₆ -alkoxy, (f) C₁ -C₆ -alkyl-S--, (g) C₂ -C₆ -alkenyl, (h) C₂ -C₆ -alkynyl, (i) C₃ -C₇ -cycloalkyl, (j) aryl, where aryl is as defined in R⁴ (c) below, or (k) aryl-C₁ -C₆ -alkyl, where aryl is as defined in R⁴ (c) below; R^(3a) is:(a) H, (b) Cl, Br, I, F, (c) C₁ -C₆ -alkyl, (d) C₁ -C₆ -alkoxy, or (e) C₁ -C₆ -alkoxyalkyl; R^(3b) is:(a) H, (b) Cl, Br, I, F, (c) C₁ -C₆ -alkyl, (d) C₃ -C₇ -cycloalkyl, (e) C₁ -C₆ -alkoxy, (f) CF₃, (g) C₂ -C₆ -alkenyl, or (h) C₂ -C₆ -alkynyl; R⁴ is:(a) H, (b) (C₁ -C₆)-alkyl, optionally substituted with a substituent selected from the group consisting of: C₁ -C₄ -alkoxy, aryl, where aryl is as defined in R⁴ (c) below, heteroaryl, where heteroaryl is as defined below, --CON(R¹⁰)₂, --N(R¹⁰)₂, --O--COR¹⁰ and --COR¹⁰ or (c) aryl, wherein aryl is phenyl or naphthyl, either unsubstituted or substituted with one or two substituents selected from the group consisting of Cl, F, Br, I, N(R⁷)₂, NR⁷ COOR⁹, NR⁷ CONR⁷ R⁹, CO₂ R⁷, CONR⁷ R⁹, C₁ -C₄ -alkyl, --(C₁ -C₄)alkyl-Y, NO₂, OH, CF₃, C₁ -C₄ -alkoxy, --S(O)_(X) --(C₁ -C₄)alkyl, and --(C₁ -C₄)alkyl-N-(CH₂ --CH₂)₂ Q, (d) heteroaryl, wherein heteroaryl is defined as pyridyl, and wherein the heteroaryl is unsubstimted or substituted with one or two substituents selected from the group consisting of: --OH, --SH, --C₁ -C₄ -alkyl, --C₁ -C₄ -alkoxy, --CF₃, Cl, Br, F, I, --NO₂, --CO₂ H, --CO₂ --(C₁ -C₄ -alkyl), --NH₂, --NH(C₁ -C₄ -alkyl) and --N(C₁ -C₄ -alkyl)₂, NR⁷ COOR⁹ and NR⁷ CONR⁷ R⁹, (e) C₃ -C₇ -cycloalkyl, or (f) --COaryl, where aryl is as defined in R⁴ (c) above; Q is:a single bond, --CH₂ --, O, NR⁷, or S(O)_(X) ; Y is:COOR⁹, CN, NR⁷ COOR⁹ or CONR⁷ R⁹ ; R⁵ and R⁶ are independently:(a) H, (b) C₁ -C₆ -alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: --OH, -guanidino, C₁ -C₄ -alkoxy, --N(R⁷)₂, COOR⁷, --CON(R⁷)₂, --O--COR⁷, -aryl, where aryl is as defined in R⁴ (c) above, -heteroaryl, where heteroaryl is as defined in R⁴ (d) above, --S(O)_(X) --R⁹, -tetrazol-5-yl, --CONHSO₂ R⁹,--SO₂ NH-heteroaryl, where heteroaryl is as defined in R⁴ (d) above, --SO₂ NHCOR⁹, --PO(OR⁷)₂, --PO(OR⁸)R⁷, --SO₂ NH--CN, --NR⁸ COOR⁹, morpholino, N-(C₁ -C₆ -alkyl)-piperazinyl, and --COR⁷, (c) --CO-aryl, where aryl is as defined in R⁴ (c) above, (d) --C₃ -C₇ -cycloalkyl, (e) Cl, Br, I, F, (f) --OH, (g) --OR⁹, (h) --C₁ -C₄ -Perfluoroalkyl, (i) --S(O)_(X) --R⁹, (j) --COOR⁷, (k) --SO₃ H, (l) --NR⁷ R⁹, (m) --NR⁷ COR⁹, (n) --NR⁷ COOR⁹, (o) --SO₂ NR⁷ R⁸, (p) --NO₂, (q) --NR⁷ SO₂ R⁹, (r) --NR⁷ CONR⁷ R⁹, (s) --OCONR⁹ R⁷, (t) -aryl, where aryl is as defined in R⁴ (c) above, (u) --NHSO₂ CF₃, (v) --SO₂ NH-heteroaryl, where heteroaryl is as defined in R⁴ (d) above, (w) --SO₂ NHCOR⁹, (x) --CONHSO₂ R⁹, (y) --PO(OR⁷)₂, (z) --PO(OR⁸)R⁷, (aa) -tetrazol-5-yl, (bb) --CONH(tetrazol -5-yl), (cc) --COR⁷, (dd) --SO₂ NHCN, (ee) --CO-heteroaryl, where heteroaryl is as defined in R4(d) above, (ff) --NR⁷ SO₂ NR⁹ R⁷, (gg) --N[CH₂ CH₂ ]₂ NR¹¹, (hh) --N[CH₂ CH₂ ]₂ O, or (ii) -heteroaryl, where heteroaryl is as defined in R4(d) above; x is:
 0. 1, or 2,R⁷ is:H, C₁ -C₅ -alkyl, aryl, or --CH₂ -aryl, where aryl is as defined in R⁴ (c) above; R⁸ is:H, or C₁ -C₄ -alkyl; R⁹ is:(a) aryl, where aryl is as defined in R⁴ (c) above, (b) heteroaryl, where heteroaryl is as defined in R⁴ (d) above, (c) C₃ -C₇ -cycloalkyl, (d) C₁ -C₈ -alkyl, wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of: aryl, where aryl is as defined in R⁴ (c) above, heteroaryl, where heteroaryl is as defined in R⁴ (d) above, --OH, --SH, C₁ -C₄ -alkyl, --O(C₁ -C₄ -alkyl), --S (C₁ -C₄ -alkyl), --CF₃, Cl, Br, F, I, --NO₂, --CO₂ H, --CO₂ --C₁ -C₄ -alkyl, --NH₂, --NR⁷ CO₂ R¹⁰, --NH(C₁ -C₄ -alkyl), --N(C₁ -C₄ -alkyl)₂, --PO₃ H₂, --PO(OH)(O--C₁ -C₄ -alkyl), --PO(OR⁸)R⁷, --NR⁷ COR¹⁰, --CONR⁷ R¹⁰, --OCONR⁷ R¹⁰, --SO₂ NR⁷ R¹⁰, --NR⁷ SO₂ R¹⁰, --N(CH₂ --CH₂)₂ Q and --CON(CH₂ --CH₂)₂ Q or (e) perfluoro-C₁ -C₄ -alkyl; R¹⁰ is:(a) aryl, where aryl is as defined in R⁴ (c) above, (b) heteroaryl, where heteroaryl is as defined in R⁴ (d) above, (c) C₁ -C₆ -alkyl, wherein alkyl is unsubstimted or substituted with a substituent selected from the group consisting of: aryl, where aryl is as defined in R⁴ (c) above, heteroaryl, where heteroaryl is as defined in R⁴ (d) above, --OH,--NH₂, --NH(C₁ -C₄ -alkyl), --N(C₁ -C₄ -alkyl)₂, --CO₂ R⁷, Cl, Br, F, I, and --CF₃, or (d) perfluoro-C₁ -C₄ -alkyl; R¹¹ is:C₁ -C₆ -alkyl, C₃ -C₇ -cycloalkyl, --CONR⁷ R⁸, heteroaryl, where heteroaryl is as defined in R⁴ (d) above, phenyl, --CO--C₃ -C₇ -cycloalkyl, or --CO--C₁ -C₆ -alkyl; and r is:1or2.
 2. The compound of claim 1, wherein:R¹ is:(a) --NHSO₂ NHCOR⁹, or (b) --NHCONHSO₂ R⁹ ; R^(2a) is:H; R^(2b) is:H, F, Cl, CF₃, C₁ -C₆ -alkyl, C₂ -C₄ -alkenyl, or C₂ -C₄ -alkynyl, aryl, wherein aryl is phenyl or naphthyl, either unsubstituted or substituted with one or two substituents selected from the group consisting of Cl, F, Br, I, N(R⁷)₂, NR⁷ COOR⁹, NR⁷ CONR⁷ R⁹,CO₂ R⁷, CONR⁷ R⁹,C₁ -C₄ -alkyl, -(C₁ -C₄)alkyl-Y, NO₂, OH, CF₃, C₁ -C₄ -alkoxy, --S(O)_(X) --(C₁ -C₄)alkyl, and --(C₁ -C₄)alkyl-N-(CH₂ --CH₂)₂ Q, or aryl-C₁ -C₆ alkyl, where aryl is as defined above; R^(3a) is:H; R^(3b) is:H, F, Cl, CF₃, C₁ -C₄ -alkyl, C₂ -C₄ -alkenyl, C₂ -C₄ -alkynyl, or C₅ -C₆ -cycloalkyl; R⁵ and R⁶ are each independently:(a) H, (b) C₁ -C₆ -alkyl unsubstimted or substituted with COOR⁷, OCOR⁷, OH, or aryl, where aryl is as defined in R^(2b) above, (c) --OH, (d) --NO₂, (e) --NHCOR⁹, (f) --C₁ -C₄ -alkoxy, (g) --NHCO₂ ^(R) ⁹, (h) --NR⁷ R⁹, (i) --Cl, F, Br, (j) --CF₃, (k) --CO₂ R⁷, (l) --CO-aryl, where aryl is as defined in R^(2b) above, (m) --S(O)_(X) --C₁ -C₄ -alkyl, (n) --S₀₂ --NH--C₁ -C₄ -alkyl, (o) --SO₂ --NH-aryl, where aryl is as defined in R^(2b) above, (P) --NHSO₂ CH₃, (q) -aryl, where aryl is as defined in R^(2b) above, (r) --NHCONR⁷ R⁹, (s) --N[CH₂ CH₂ ]₂ NR¹¹, or (t) --N[CH₂ CH]₂ O; r isone.
 3. The compound of claim 2, wherein:R¹ is:(a) --NHSO₂ NHCOR⁹, or (b) --NHCONHSO₂ R⁹ ; R⁴ is:H, (C₁ -C₆)-alkyl, aryl, wherein aryl is phenyl or naphthyl, either unsubstimted or substituted with one or two substituents selected from the group consisting of Cl, F, Br, I, N(R⁷)₂, NR⁷ COOR⁹, NR⁷ CONR⁷ R⁹, CO₂ R⁷, CONR⁷ R⁹,C₁ -C₄ -alkyl, --(C₁ -C₄)alkyl-Y, NO₂, OH, CF₃, C₁ -C₄ -alkoxy, --S(O)_(X) --(C₁ -C₄)alkyl, and-(C₁ -C₄)alkyl-N-(CH₂ --CH₂)₂ Q, or aryl-(C₁ -C₆)-alkyl, where aryl is as defined above, or heteroaryl, wherein heteroaryl is defined as pyridyl and wherein the heteroaryl is unsubstimted or substituted with one or two substituents selected from the group consisting of: --OH, --SH, --C₁ -C₄ -alkyl, --C₁ -C₄ -alkoxy, --CF₃, Cl, Br, F, I, --NO₂, --CO₂ H, --CO₂ --(C₁ -C₄ -alkyl), --NH₂, --NH(C₁ -C₄ -alcyl) and --N(C₁ -C₄ -alkyl)₂, NR⁷ COOR⁹ and NR⁷ CONR⁷ R⁹ ; and R⁵ and R⁶ are each independently:H, --C₁ -C₄ -alkyl, -aryl, where aryl is as defined in R⁴ above, --NO₂, --NR⁷ R⁹, --NHCOOR⁹, --Cl, CH₂ COOH, --S(O)_(X) --C₁ -C₄ -alkyl, NHCONR⁷ R⁹, NHCOR⁹, CO₂ R⁹, --F, N[CH₂ CH₂ ]₂ NR¹¹, or N[CH₂ CH₂ ]₂ O.
 4. The compound of claim 1, wherein:R¹ is:(a) --SO₂ NHR⁹, (b) --SO₂ NHCOR⁹, (c) --SO₂ NHCONR⁷ R⁹,or (d) --SO₂ NHCOOR⁹ ; R^(2a) is:H; R^(2b) is:H, F, Cl, CF₃, C₁ -C₆ -alkyl, C₂ -C₄ -alkenyl, or C₂ -C₄ -alkynyl, aryl, wherein aryl is phenyl or naphthyl, either unsubstituted or substituted with one or two substituents selected from the group consisting of Cl, F, Br, I, N(R⁷)₂, NR⁷ COOR⁹, NR⁷ CONR⁷ R⁹, CO₂ R⁷, CONR⁷ R⁹, C₁ -C₄ -alkyl, --(C₁ -C₄)alkyl-Y, NO₂, OH, CF₃, C₁ -C₄ -alkoxy, --S(O)_(X) --(C₁ -C₄)alkyl, and --(C₁ -C₄)alkyl-N-(CH₂ --CH₂)₂ Q, or aryl-C₁ -C₆ -alkyl, where aryl is as defined above; R^(3a) is:H; R³ is:H, F, Cl, CF₃, C₁ -C₄ -alkyl, C₂ -C₄ -alkenyl, C₂ -C₄ -alkynyl, or C₅ -C₆ -cycloalkyl; R⁵ and R⁶ are independently:(a) H, (b) C₁ -C₆ -alkyl, unsubstituted or substituted with COOR⁷, OCOR⁷, OH, or aryl, where aryl is as defined in R^(2b) above, (c) --OH, (d) --NO₂, (e) --NHCOR⁹, (f) --C₁ -C₄ -alkoxy, (g) --NHCO₂ R⁹, (h) --NR⁷ R⁹, (i) --Cl, F, Br, (j) --CF₃, (k) --CO₂ R⁷, (l) --CO-aryl, where aryl is as defined in R^(2b) above, (m) --S(O)_(X) --C₁ -C₄ -alkyl, (n) --SO₂ --NH--C₁ -C₄ -alkyl, (o) --SO₂ --NH-aryl, where aryl is as defined in R^(2b) above, (P) --NHSO₂ CH₃, (q) -aryl, where aryl is as defined in R^(2b) above, (r) --NHCONR⁷ R⁹, (s) --N[CH₂ CH₂ ]₂ NR¹¹, or (t) --N[CH₂ CH₂ ]₂ O; and r isone.
 5. The compound of claim 4, wherein:R¹ is:(a) --SO₂ NHR⁹, (b) --SO₂ NHCOR⁹, (c) --SO₂ NHCONR⁷ R⁹, or (d) --SO₂ NHCOOR⁹ ; R⁴ is:H, (C₁ -C₆)-alkyl, aryl, wherein aryl is phenyl or naphthyl, either unsubstimted or substituted with one or two substituents selected from the group consisting of Cl, F, Br, I, N(R⁷)₂, NR⁷ COOR⁹, NR⁷ CONR⁷ R⁹, CO₂ R⁷, CONR⁷ R⁹,C₁ -C₄ -alkyl, --(C₁ -C₄)alkyl-Y, NO₂, OH, CF₃, C₁ -C₄ -alkoxy, --S(O)_(X) --(C₁ -C₄)alkyl, and --(C₁ -C₄)alkyl-N--(CH₂ --CH₂)₂ Q, or aryl-(C₁ -C₆)-alkyl, where aryl is as defined above, or heteroaryl, wherein heteroaryl is defined as pyridyl and wherein the heteroaryl is unsubstimted or substituted with one or two substituents selected from the group consisting of: --OH, --SH, --C₁ -C₄ -alkyl, --C₁ -C₄ -alkoxy, --CF₃, Cl, Br, F, I, --NO₂, --CO₂ H, --CO₂ --(C₁ -C₄ -alkyl), --NH₂, --NH(C₁ -C₄ -alkyl) and --N(C₁ -C₄ -alkyl)₂, NR⁷ COOR⁹ and NR⁷ CONR⁷ R⁹ ; and R⁵ and R⁶ are each independently:H, --C₁ -C₄ -alkyl, -aryl, where aryl is as defined in R⁴ above, --NO₂, --NR⁷ R⁹, --NHCOOR⁹, --Cl, --CH₂ COOH, --S(O)_(X) --C₁ -C₄ -alkyl, NHCONR⁷ R⁹, NHCOR⁹, CO₂ R⁷, --F, N[CH₂ CH₂ ]₂ NR¹¹, or N[CH₂ CH₂ ]₂ O.
 6. A compound of structural formula ##STR20## wherein the substituents are as defined in Table 1 below and Boc is defined as N-tert-butoxycarbonyl and Ac is defined as acetyl:

                  TABLE I                                                          ______________________________________                                         R.sup.4    R.sup.5 R.sup.6 R.sup.9                                             ______________________________________                                         H          H       H       --(CH.sub.2).sub.5 NHBoc                            H          H       H       --(CH.sub.2).sub.5 NH.sub.2                         Methyl     H       H       --(CH.sub.2).sub.5 NHBoc                            Methyl     H       H       --(CH.sub.2).sub.5 NH.sub.2                         n-Propyl   H       i-propyl                                                                               --(CH.sub.2).sub.5 NHBoc                            n-Propyl   H       H       --(CH.sub.2).sub.5 NHBoc                            n-Propyl   H       H       --(CH.sub.2).sub.5 NH.sub.2                         i-Propyl   H       H                                                           cyclopropyl                                                                    i-Propyl   H       H       --(CH.sub.2).sub.4 NHBoc                            i-Propyl   H       H       --(CH.sub.2).sub.4 NH.sub.2                         Phenyl     H       H                                                           cyclopropyl                                                                    Phenyl     H       H       --(CH.sub.2).sub.5 NHBoc                            Phenyl     H       H       --(CH.sub.2).sub.5 NH.sub.2                         Phenyl     methyl  H       --(CH.sub.2).sub.5 NHBoc                            Phenyl     methyl  H       --(CH.sub.2).sub.5 NH.sub.2                         p-Toluyl   H       H       --(CH.sub.2).sub.5 NHCOCH.sub.3                     p-Toluyl   H       methyl  --(CH.sub.2).sub.5 NH.sub.2                         p-Toluyl   H       methyl  --(CH.sub.2).sub.5 NHBoc                            4-Cl-Phenyl                                                                               H       H       --(CH.sub.2).sub.5 NHBoc                            4-Cl-Phenyl                                                                               H       H       --(CH.sub.2).sub.5 NH.sub.2                         4-Cl-Phenyl                                                                               H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2              4-Cl-Phenyl                                                                               H       methyl  --(CH.sub.2).sub.5 NHBoc                            4-Br-Phenyl                                                                               H       H       --(CH.sub.2).sub.5 NHBoc                            4-Br-Phenyl                                                                               H       H       --(CH.sub.2).sub.5 NH.sub.2                         4-F-Phenyl H       H       --(CH.sub.2).sub.5 NHBoc                            4-F-Phenyl H       H       --(CH.sub.2).sub.5 NH.sub.2                         4-OMe-Phenyl                                                                              H       H       --(CH.sub.2).sub.5 NHBoc                            4-OMe-Phenyl                                                                              H       H       --(CH.sub.2).sub.5 NH.sub.2                         p-Toluyl   H       H       --(CH.sub.2).sub.5 NHBoc                            p-Toluyl   H       H       --(CH.sub.2).sub.5 NH.sub.2                         p-Toluyl   H       H       --(CH.sub.2).sub.6 NHBoc                            p-Toluyl   H       H       --(CH.sub.2).sub.6 NH.sub.2                         p-Toluyl   H       H       --(CH.sub.2).sub.3 NHBoc                            p-Toluyl   H       H       --(CH.sub.2).sub.3 NH.sub.2                         p-Toluyl   H       H       --(CH.sub.2).sub.4 NHBoc                            P-Toluyl   B       H       --(CH.sub.2).sub.4 NH.sub.2                         p-Toluyl   H       H       --(CH.sub.2).sub.6 OH                               p-Toluyl   H       H       --(CH.sub.2).sub.5 COOC.sub.2 H.sub.5               p-Toluyl   H       H       --(CH.sub.2).sub.4 COOH                             p-Toluyl   methyl  H       --(CH.sub.2).sub.5 COOC.sub.2 H.sub.5               p-Toluyl   H       H       --(CH.sub.2).sub.6 CH.sub.3                         p-Toluyl   H       H       --(CH.sub.2).sub.5 CONHCH.sub.3                     p-Toluyl   H       H       --(CH.sub.2).sub.5 CON(CH.sub.3).sub.2              p-Toluyl   H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2              p-Toluyl   H       H       --(CH.sub.2).sub.4 CON(CH.sub.2).sub.4              p-Toluyl   H       H       --(CH.sub.2).sub.4 CON(CH.sub.2).sub.5              p-Toluyl   H       H       --(CH.sub.2).sub.4 CON(CH.sub.2 CH.sub.2).sub.2                                 O                                                  p-Toluyl   H       H       --(CH.sub.2).sub.4 CON(CH.sub.2 CH.sub.2).sub.2                                 NH                                                 p-Toluyl   H       H       --(CH.sub.2).sub.4 CON(CH.sub.2 CH.sub.2).sub.2                                 NAc                                                p-Toluyl   H       H       --(CH.sub.2).sub.4 CON(CH.sub.2 CH.sub.2).sub.2                                 NCH.sub.3                                          p-Toluyl   H       H       --(CH.sub.2).sub.6 CON(CH.sub.3).sub.2              p-Toluyl   H       H       --(CH.sub.2).sub.2 CH(NHBoc)COOtBu                  p-Toluyl   H       H                                                           2-thienyl                                                                      p-Toluyl   H       H                                                           3-furyl                                                                        p-Toluyl   H       H                                                           2-furyl                                                                        p-Toluyl   H       H       --(CH.sub.2).sub.2 OCH.sub.3                        p-Toluyl   H       H       --NH(CH.sub.2).sub.3 CH.sub.3                       p-Toluyl   H       H       --NH(CH.sub.2).sub.5 CH.sub.3                       p-Toluyl   H       H       --NH(CH.sub.2).sub.3 Cl                             p-Toluyl   H       H       --NH(CH.sub.2).sub.2 -2-thienyl                     p-Toluyl   H       H       --CH.sub.2 OCH.sub.2 CH.sub.3                       p-Toluyl   H       H       --(CH.sub.2).sub.5 OH                               p-Toluyl   H       H       --NH(CH.sub.2).sub.5 CH.sub.3                       p-Toluyl   H       H       --(CH.sub.2).sub.5 N(CH.sub.3).sub.2                p-Toluyl   H       H       --(CH.sub.2).sub.5 NHCH.sub.3                       1-Naphthyl H       H       --(CH.sub.2).sub.5 N(CH.sub.3).sub.2                1-Naphthyl H       H       --(CH.sub.2).sub.5 CON(CH.sub.3).sub.2              1-Naphthyl H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2              1-Naphthyl H       H       --(CH.sub.2).sub.5 NHBoc                            1-Naphthyl H       H       --(CH.sub.2).sub.5 NH.sub.2                         4-OMe-Phenyl                                                                              H       H       --(CH.sub.2).sub.5 CON(CH.sub.3).sub.2              4-OMe-Phenyl                                                                              H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2              2-Naphthyl H       H       --(CH.sub.2).sub.5 N(CH.sub.3).sub.2                2-Naphthyl H       H       --(CH.sub.2).sub.5 CON(CH.sub.3).sub.2              2-Naphthyl H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2              2-Naphthyl H       H       --(CH.sub.2).sub.5 NHBoc                            2-Naphthyl H       H       --(CH.sub.2).sub.5 NH.sub.2                         Pentamethylphenyl                                                                         H       H       --(CH.sub.2).sub.5 NH.sub.2                         Pentamethylphenyl                                                                         H       H       --(CH.sub.2).sub.5 NHBoc                            Pentamethylphenyl                                                                         H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2              2-pyridyl  H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2              4-pyridyl  H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2              2-Thienyl  H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2              2-pyridyl  H       H       --(CH.sub.2).sub.5 NHBoc                            2-pyridyl  H       H       --(CH.sub.2).sub.5 NH.sub.2                         2-pyridyl  H       H       --(CH.sub.2).sub.5 N(CH.sub.3).sub.2                4-pyridyl  H       H       --(CH.sub.2).sub.5 NHBoc                            4-pyridyl  H       H       --(CH.sub.2).sub.5 NH.sub.2                         4-pyridyl  H       H       --(CH.sub.2).sub.5 N(CH.sub.3).sub.2                4-pyridyl  H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2              2-Thienyl  H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2              4-(N-Morpholino-                                                                          H       H       --(CH.sub.2).sub.5 NHBoc                            methyl)phenyl                                                                  4-(N-Morpholino-                                                                          H       H       --(CH.sub.2).sub.5 NH.sub.2                         methyl)phenyl                                                                  4-(N-Pyrrolidino-                                                                         H       H       --(CH.sub.2).sub.5 NHBoc                            methyl)phenyl                                                                  4-(N-Pyrrolidino-                                                                         H       H       --(CH.sub.2).sub.5 NH.sub.2                         methyl)phenyl                                                                  4-(N-Pyrrolidino-                                                                         H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2              methyl)phenyl                                                                  4-(N-Morpholino-                                                                          H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2              methyl)phenyl                                                                  p-Toluyl   H       H       --(CH.sub.2).sub.3 CON(CH.sub.3).sub.2              p-Toluyl   H       H       --(CH.sub.2).sub.5 NHCON(CH.sub.3).sub.2            p-Toluyl   H       H       --(CH.sub.2).sub.5 NHSO.sub.2 iPr                   p-Toluyl   H       H       --(CH.sub.2).sub.3 NHCON(CH.sub.3).sub.2            p-Toluyl   H       H       --NH(CH.sub.2).sub.3 CON(CH.sub.3).sub.2            p-Toluyl   H       H       --(CH.sub.2).sub.3 NHCOCH.sub.3                     p-Toluyl   H       H       --(CH.sub.2).sub.4 CONH.sub.2                       p-Toluyl   H       H       --(CH.sub.2).sub.4 CONHCH.sub.3                     4-Cl-Phenyl                                                                               H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2              4-F-Phenyl H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2              2-CH.sub.3 CONH-                                                                          H       H       --(CH.sub.2).sub.4 CON(CH.sub.3).sub.2.--           Phenyl                                                                         ______________________________________                                     